N-containing condensed heterocyclic compounds, their production, and their uses

ABSTRACT

N-containing, condensed heterocyclic compounds and salts thereof are disclosed which are useful for inhibiting squalene synthetase and fungal growth, and which are useful for treating or preventing hyperlipidemia. Also disclosed is a method for producing these compounds.

This application is a divisional of application Ser. No. 08/338,163filed Nov. 9, 1994 now U.S. Pat. No. 5,526,306, which is a CIP ofapplication Ser. No. 08/195,131 filed Feb. 9, 1994, now abandoned, whichis a continuation of application Ser. No. 08/049,455 filed Apr. 20,1993, now abandoned.

FIELD OF THE INVENTION

This invention relates to N-containing, condensed heterocyclic compoundsor salts which are useful for inhibiting squalene synthetase and fungalgrowth, and which are useful for treating or preventing hyperlipidemia,and the production thereof.

BACKGROUND OF THE INVENTION

Hypercholesteremia, high blood pressure and smoking are known as threemajor, dangerous factors causing ischemic diseases. Adequate control ofcholesterol concentration in blood is remarkably important for theprophylaxis or therapy of, not only ischemic diseases, but also coronarysclerosis.

Abnormal elevations of lipid levels in the serum or the plasma arecalled hyperlipidemia or hyperlipemia. There are various lipids, such ascholesterol (cholesteryl ester and free cholesterol), phospholipids(lecithin, sphingomyelin and so on), triglyceride, free fatty acids andother sterols in the serum or the plasma. Especially cholesterol andtriglyceride are clinically important among them.

Therefore, it is important to control blood lipid levels within normalrange for the treatment and the prevention of various diseases relatedto atherosclerosis, such as coronary heart disease and cerebralinfarction. Hypertriglyceridemia is also related to the development ofpancreatitis.

As pharmaceutical compositions for lowering cholesterol in blood,attention has been drawn to those for controlling the biosynthesis ofcholesterol, besides those of inhibiting its absorption by binding bileacid including, among others, cholestyramine, colestipol (disclosed in,for example, U.S. Pat. No. 4,027,009), and those of suppressing theintestinal absorption of cholesterol by inhibiting acyl coenzyme Acholesterol acyl transferase (ACAT) including melinamide (disclosed inFrench Patent No.1476569). As pharmaceutical preparations forcontrolling the biosynthesis of cholesterol, lovastatin (disclosed inU.S. Pat. No. 4,231,938), simvastatin (disclosed in U.S. Pat. No.4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which arecapable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme(HMG-CoA) reductase, are provided for medicinal use. However, whenHMG-COA reductase is inhibited, not only the biosynthesis of cholesterolbut the biosynthesis of some other components such ubiquinone, dolicholand heme A, which are necessary for the living body, is also inhibited,so that occurrences of undesirable side effects to be caused thereby arefeared.

Squalene synthetase is the enzyme involved in the committed step of thede novo cholesterol biosynthetic pathway. This enzyme catalyzes thereductive dimerization of two molecules of farnesyl pyrophosphate toform squalene.

On the other hand, the compounds expected as inhibitors of cholesterolbiosynthesis by inhibiting squalene synthetase are disclosed in JPAH1(1989)-213288, JPA H2(1990)-101088, JPA H2(1990)-235820, JPAH2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)68591, JPAH3(1991)-48288, U.S. Pat. No. 5,019,390, Journal of Medicinal Chemistry,51 (10), p.1869-1871 (1988), U.S. Pat. No. 5,135,935 and WO 9215579.

Also, the compounds expected as inhibitors of fungal growth byinhibiting squalene synthetase are disclosed in JPA H4 (1992)-279589, EP475706-A, EP 494622-A and EP 503520-A.

Among 4,1-benzoxazepine derivatives, in 4,1-benzoxazepin-2-onederivatives in which 2-position is substituted with a ketone group,those in which one of the hydrogen atoms at 3-position is replaced witha different substituent, are disclosed in JPA S57(1982)345765 and Chem.Pharm. Bull., 34, 140 (1986).

Ubiquinone, dolichol and heme A have been known as being synthesizedfrom farnesyl pyrophosphate along the cholesterol biosynthesis pathway.Therefore, for avoiding occurrence of side effects due to loss of thesesubstances, it is desirable to inhibit enzymes subsequent to farnesylpyrophosphate, especially squalene synthetase, in the cholesterolbiosynthetic pathway.

In addition, fabric acid derivatives, such as clofibrate (British patentNo. 860303) and phenofibrate (Germany patent No. 2250327), are on themarket as hypotriglyceridemic agents. But, caution is claimed againstthe combination therapy of fibrates with statins because of theheightened risk of myopathy and rhabdomyolysis.

Hyperlipidemia or hyperlipoproteinemia is classified by WHO as follows:

Type I: Hyperchyromicronemia

Type IIa: Hyper low density lipoproteinemia (Hypercholesterolemia)

Type IIb: Mixed-type hyperlipidemia which shows increases in low densitylipoprotein and very low density lipoprotein

Type III: Abnormal β-lipoproteinemia which shows the presence of β-verylow density lipoprotein

Type IV: Hyper very low density lipoproteinemia (Hypertriglyceridemia)

Type V: Mixed-type hyperlipemia which shows increases in very lowdensity lipoprotein and chyromicron

SUMMARY OF THE INVENTION

Through intensive investigations from the above viewpoint, the presentinventors found that certain N-containing, condensed heterocycliccompounds exhibit excellent squalene synthetase inhibitory action,antifungal action, and hypotriglyceridemic action, thereby resulting inthe present invention.

More specifically, the present invention is to provide a pharmaceuticalcomposition which comprises the compound represented by the formula (Ir)##STR1## wherein R₁ is hydrogen or an optionally substituted hydrocarbongroup; R₂ and R₃ independently is hydrogen, an optionally substitutedalkyl group, an optionally substituted phenyl group or an optionallysubstituted aromatic heterocyclic ring group; X' is a substituentcomprising an optionally esterified carboxyl group, an optionallysubstituted carbamoyl group, an optionally substituted hydroxyl group,an optionally substituted amino group or an optionally substitutedheterocyclic radical having a protonizable hydrogen; Ring A is anoptionally substituted benzene ring or an optionally substitutedaromatic heterocyclic ring; Ring J' is a 7- to 8-membered heterocyclicring containing at most three ring constituting hetero atoms; the RingJ' optionally having, besides R₁, R₂, R₃ and X', a further substituent,or a pharmaceutically acceptable salt thereof.

A further embodiment relates to the composition mentioned above, whereinthe compound is represented by the formula (Ir'): ##STR2## wherein R₁ ishydrogen or an optionally substituted hydrocarbon group; R₂ and R₃independently is hydrogen, an optionally substituted alkyl group, anoptionally substituted phenyl group or an optionally substitutedaromatic heterocyclic ring group; X₁ is a bond or a divalent atomicchain; Y is an optionally esterified carboxyl group, an optionallysubstituted carbamoyl group, an optionally substituted hydroxyl group,an optionally substituted amino group or an optionally substitutedheterocyclic radical having protonizable hydrogen; Ring B is anoptionally substituted benzene ring, or a pharmaceutically acceptablesalt thereof.

The compounds described above and in the following subgenericembodiments can be used as squalene synthetase inhibitors, antifungalagents, and hypotriglyceridemic agents. Preferred uses of the differentsubgeneric embodiments are listed below each of the following formulae.

Further subgeneric embodiments of the present invention include thefollowing:

(1) 4,1-Benzoxazepin-2-one derivatives represented by the formula (I):##STR3## wherein R₁ stands for hydrogen atom or an optionallysubstituted hydrocarbon group; R₂ and R₃ independently stand forhydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted phenyl group or an optionally substitutedaromatic heterocyclic group; X stands for a bond or a spacer having thechain length of 1 to 7 atoms; Y stands for an optionally esterified orthioesterified carboxyl group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted phenylgroup, an optionally substituted carbamoyl group or a N-containingheterocyclic residue having hydrogen atom capable of being deprotonated;provided that, when X is methylene and R₁ is not an alkyl group havingcarbon atoms of more than 4, Y is neither carboxyl group noralkoxycarbonyl group; and the ring A may optionally be substituted, orsalts thereof,

(2) 4,1-Benzoxazepin-2-one derivatives represented by the formula (I'):##STR4## wherein R¹ stands for hydrogen atom or an optionallysubstituted hydrocarbon group; R₂ and R₃ independently stand forhydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted phenyl group or an optionally substitutedaromatic heterocyclic group; X stands for a bond or a spacer having thechain length of 1 to 7 atoms; Y stands for an optionally esterified orthioesterified carboxyl group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted phenylgroup, an optionally substituted carbamoyl group or a N-containingheterocyclic residue having hydrogen atom capable of being deprotonated;provided that, when X is methylene, Y is neither carboxyl group noralkoxycarbonyl group; and the ring A may optionally be substituted, orsalts thereof,

(3) a squalene synthetase inhibitor comprising as an active ingredient a4,1-Benzoxazepin-2-one derivative represented by the formula (I"):##STR5## wherein R¹ stands for hydrogen atom or an optionallysubstituted hydrocarbon group; R₂ and R₃ independently stand forhydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted phenyl group or an optionally substitutedaromatic heterocyclic group; X stands for a bond or a spacer having thechain length of 1 to 7 atoms; Y stands for an optionally esterified orthioesterified carboxyl group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted phenylgroup, an optionally substituted carbamoyl group or a N-containingheterocyclic residue having hydrogen atom capable of being deprotonated;and the ring A may optionally be substituted, or a salt thereof, and

(4) a fungal growth inhibitor comprising as an active ingredient a4,1-Benzoxazepin-2-one derivative represented by the formula (I"):##STR6## wherein R¹ stands for hydrogen atom or an optionallysubstituted hydrocarbon group; R₂ and R₃ independently stand forhydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted phenyl group or an optionally substitutedaromatic heterocyclic group; X stands for a bond or a spacer having thechain length of 1 to 7 atoms; Y stands for an optionally esterified orthioesterified carboxyl group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted phenylgroup, an optionally substituted carbamoyl group or a N-containingheterocyclic residue having hydrogen atom capable of being deprotonated;and the ring A may optionally be substituted, or a salt thereof.

Further, the present invention is to provide a method of producing thenovel compounds represented by the formula (I) and (I') or saltsthereof.

In the above-mentioned formulae (I), (I') and (I"), as the hydrocarbongroup of "optionally substituted hydrocarbon group" shown by R₁, mentionis made of aliphatic chain hydrocarbon groups, alicyclic hydrocarbongroup and aryl group, among others, with preference given to aliphaticchain hydrocarbon groups.

A further aspect of the present invention is compounds of the formulae(I), (I'), and (I") wherein the chiral carbon atom directly bonded to Xpossesses the R configuration and the chiral carbon atom directly bondedto R₂ and R₃ possesses the S configuration.

Another aspect of the present invention is a compound of the formula##STR7## wherein R₁ is a lower alkyl, preferably isobutyl or neopentyl;X is hydrogen, preferably chlorine, or a metal ion, preferably a sodiumion or a potassium ion; ring A is phenyl substituted with halogen; andring B is phenyl substituted with a lower alkoxy, preferably methoxy orethoxy.

DETAILED DESCRIPTION OF THE INVENTION

In the above formulae (Ir), (Ir'), (I), (I') and (I"), as thehydrocarbon group of the "optionally substituted hydrocarbon group"shown by R¹, mention is made of aliphatic chain hydrocarbon groups,alicyclic hydrocarbon group and aryl group, among others, withpreference given to aliphatic chain hydrocarbon groups.

As the aliphatic chain hydrocarbon group of said hydrocarbon group,mention is made of straight-chain or branched aliphatic hydrocarbongroups, for example, alkyl group, alkenyl group and alkynyl group, withpreference given to lower alkyl group, lower alkenyl group and loweralkynyl group. As the lower alkyl group, C₁₋₇ lower alkyl groups arepreferable, which are exemplified by methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyland 1-ethylpropyl, with preference given to C₂₋₅ alkyl group, morepreferably C₄₋₅ alkyl groups. As the lower alkenyl group, C₂₋₆ loweralkenyl groups are preferable, which are exemplified by vinyl, allyl,2-methylallyl isopropenyl, 1-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl and 5- hexenyl. Among them, vinyl, allyl,isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,and 3-methyl-2-butenyl are especially preferable. As the lower alkynylgroup, C₂₋₆ lower alkynyl groups are preferable, which are exemplifiedby ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl and 5-hexynyl. Among them, ethynyl, 1-propynyl and2-propynyl are especially preferable.

As the alicyclic hydrocarbon group of the said hydrocarbon group,mention is made of saturated or unsaturated alicyclic hydrocarbongroups, which are exemplified by cycloalkyl group, cycloalkenyl group orcycloalkadienyl group. As the cycloalkyl group, C₃₋₉ cycloalkyl groupsare preferable, which are exemplified by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl. Amongthem, C₃₋₆ cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl are especially preferable. Examples of thecycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and1-cyclopenten-1-yl. Examples of the cycloalkadienyl group include2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and2,5-cyclohexadien-1-yl.

As the aryl group of said hydrocarbon group, mention is made ofmonocyclic or condensed polycyclic aromatic hydrocarbon groups, whichare exemplified by phenyl, naphthyl, anthryl, phenanthryl andacenaphthylenyl. Among them, phenyl, 1-naphthyl and 2-naphthyl areespecially preferable.

As the substituent of "optionally substituted hydrocarbon group" shownby R₁, mention is made of optionally substituted aryl groups, optionallysubstituted cycloalkyl groups or cycloalkenyl groups, optionallysubstituted heterocyclic groups, optionally substituted amino groups,optionally substituted hydroxyl groups, optionally substituted thiolgroups and halogen atoms (e.g. fluorine, chlorine, bromine and iodine).Number of these optional substituents ranges from 1 to 5 (preferably 1to 3). As the aryl group of said optionally substituted aryl group,mention is made of phenyl, naphthyl, anthryl, phenanthryl andacenaphthylenyl. Among them, phenyl, 1-naphthyl and 2-naphthyl arepreferable. As the substituent on said optionally substituted arylgroup, mention is made of C₁₋₃ alkoxy groups (e.g. methoxy, ethoxy andpropoxy), halogen atoms (e.g. fluorine, chlorine bromine and iodine) andC₁₋₃ alkyl groups (e.g. methyl, ethyl and propyl). Number of theseoptional substituents ranges from 1 to 2. As the cycloalkyl group ofsaid optionally substituted cycloalkyl group, mention is made of C₃₋₇cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. Kinds and number of the substituents on saidoptionally substituted cycloalkyl group are the same as those mentionedfor the substituents in the above-mentioned optionally substituted arylgroups. As the cycloalkenyl group of said optionally substitutedcycloalkenyl group, mention is made of C₃₋₆ cycloalkenyl groupsincluding cyclopropanyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.Kinds and number of the substituents on said optionally substitutedcycloalkenyl group are the same as those mentioned for the substituentsin the above-mentioned optionally substituted aryl groups. As theheterocyclic group of said optionally substituted heterocyclic group,mention is made of an aromatic heterocyclic group and a saturated orunsaturated non-aromatic heterocyclic group (aliphatic heterocyclicgroup) having at least one hetero atom selected from oxygen, sulfur andnitrogen, with preference given to an aromatic heterocyclic group. Assaid aromatic heterocyclic group, mention is made of aromatic monocyclicheterocyclic groups (e.g. furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.) and aromatic condensedheterocyclic groups (e.g. benzofuranyl, isobenzofuranyl, benzob!thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxthinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, 1,2,4-triazolo4,3-b!pyridazinyl, etc.), with preference given to furyl, thienyl,pyridyl, pyrimidinyl, pyrazinyl, indolyl and isoindolyl. As saidnon-aromatic heterocyclic group, mention is made of, for example,oxiranyl, azetidinyl, oxetanyl, thiethanyl, pyrrolidinyl,tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl, etc. As the substituent of said optionallysubstituted heterocyclic group, mention is made of C₁₋₃ alkyl groups(e.g. methyl, ethyl and propyl). As the substituent of said optionallysubstituted amino group, optionally substituted hydroxyl group oroptionally substituted thiol group, mention is made of C₁₋₃ alkyl groups(e.g. methyl, ethyl and propyl). In the case where the hydrocarbon groupin the optionally substituted hydrocarbon group shown by R₁ is analicyclic hydrocarbon group or aryl group, it may further have a C₁₋₃alkyl group (e.g. methyl, ethyl and propyl).

Further examples of R₁ include optionally substituted C₁₋₄ acyl groupssuch as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, dimethylacetyl, and trimethylacetyl.Said acyl group may have one to five substituents at any possibleposition. Such substituents include halogen atoms (e.g. fluorine,chlorine, and bromine).

In the above-mentioned formulae, as the optionally substituted loweralkyl groups shown by R₂ and R₃, mention is made of C₁₋₆ lower alkylgroups (e.g. methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl andisohexyl), preferably C₁₋₄ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl and t-butyl. As the substituent of said optionallysubstituted lower alkyl group, mention is made of

halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C₁₋₄ loweralkoxy groups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy andt-butoxy), among others.

Substituents of "optionally substituted phenyl group" shown by R₂ and R₃are independently exemplified by halogen atom (e.g. fluorine, chlorine,bromine or iodine), optionally substituted C₁₋₄ lower alkyl groups (e.g.methyl, ethyl, propyl, isopropyl, butyl and t-butyl), optionallysubstituted C₁₋₄ lower alkoxy groups (e.g. methoxy, ethoxy, propoxy,isopropoxy, butoxy and t-butoxy), optionally substituted hydroxyl group,nitro group and cyano group, and "optionally substituted phenyl group"may have 1 to 3 of these substituents. As the substituent of saidoptionally substituted lower (C₁₋₄) alkyl group or optionallysubstituted (C₁₋₄) alkoxy group, mention is made of, among others,halogen atoms (e.g. fluorine, chlorine, bromine, iodine), and 1 to 3 ofthem may be substituted on optional positions. As the substituent ofoptionally substituted hydroxyl group, mention is made of, among others,lower (C₁₋₄) alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyland t-butyl), C₃₋₆ cycloalkyl groups (e.g. cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), aryl groups (e.g. phenyl, 1-naphthyl and2-naphthyl) and aralkyl groups (e.g. benzyl, phenethyl). Further, twoadjoining substituents on the phenyl group may cooperate therewith toform a ring. Examples of such rings are the following formulae: ##STR8##The above ring formed by two adjoining substituents may itself besubstituted with a lower (C₁₋₃) alkyl (e.g. methyl, ethyl, propyl, andisopropyl) and the like.

As the aromatic heterocyclic group of "optionally substituted aromaticheterocyclic group" shown by R₂ and R₃, mention is made of the samearomatic heterocyclic groups specified for R₁. Among them, furyl,thienyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, andisoindolyl are preferred. As the substituent of said aromaticheterocyclic group, mention is made of lower C₁₋₃ alkyl groups (e.g.methyl, ethyl, and propyl), among others.

Among the above-exemplified groups represented by R₂ and R₃, optionallysubstituted phenyl groups, substituted phenyl groups are preferable,with greater preference given to a phenyl group substituted with halogenand lower alkoxy. Also, either R₂ or R₃ is preferably hydrogen.

In the above formulae (Ir), as the "a substituent comprising anoptionally esterified carboxyl group" shown by X', mention is made ofoptionally esterified carboxyl groups and a substituent having anoptionally esterified carboxyl group, etc. Said optionally esterifiedcarboxyl groups are substantially the same as those in the case of thebelow-mentioned optionally esterified carboxyl groups shown by Y.

As the "a substituent comprising an optionally substituted carbamoylgroup" shown by X', mention is made of optionally substituted carbamoylgroups and a substituent having an optionally substituted carbamoylgroup, etc. Said optionally substituted carbamoyl groups aresubstantially the same as those in the case of the below-mentionedoptionally substituted carbamoyl groups shown by Y.

As the "a substituent comprising an optionally substituted hydroxylgroup" shown by X', mention is made of optionally substituted hydroxylgroups and a substituent having an optionally substituted hydroxylgroup, etc. Said optionally substituted hydroxyl groups aresubstantially the same as those in the case of the below-mentionedoptionally substituted hydroxyl groups shown by Y.

As the "a substituent comprising an optionally substituted amino group"shown by X', mention is made of optionally substituted amino groups anda substituent having an optionally substituted amino group, etc. Saidoptionally substituted amino groups are substantially the same as thosein the case of the below-mentioned optionally substituted amino groupsshown by Y.

As the "substituent comprising an optionally substituted heterocyclicradical having a protonizable hydrogen" shown by X', mention is made ofan optionally substituted heterocyclic radical having a protonizablehydrogen and a substituent having an optionally substituted heterocyclicradical having a protonizable hydrogen, etc. Said optionally substitutedheterocyclic radicals are substantially the same as those in the case ofthe below-mentioned optionally substituted heterocyclic radicals shownby Y.

Examples of X' include groups represented by the formula (a)

    ......... X--Y

wherein X is a bond or a divalent or trivalent atomic chain; Y is anoptionally esterified carboxyl group, an optionally substitutedcarbamoyl group, an optionally substituted hydroxyl group, an optionallysubstituted amino group or an optionally substituted heterocyclicradical having a protonizable hydrogen; the symbol ......... is a singleor double bond.

In addition , as X, mention is made of a carbon chain containing adouble bond or --L--C(OH)-- (wherein L is a bond or a straight-chain orbranched alkylene chain). As said "carbon chain containing double bond",mention is made of, preferably, those in which the carbon numberconstituting the straight-chain portion ranges from 1 to 7, morepreferably 1 to 4, and they may optionally have a side chain. While thedouble bond at said carbon chain is contained in the straight-chainportion and/or branched chain portion, it is contained preferably in thestraight-chain portion. Number of the double bond contained in saidcarbon chain is not restricted as far as possible, it ranges preferablyfrom 1 to 2.

Examples of carbon chains containing said double bond include methine,vinylene, propenylene, butenylene, butadienylene, methylpropenylene,ethylpropenylene, propylpropenylene, methylbutenylene, ethylbutenylene,propylbutenylene, methylbutadienylene, ethylbutadienylene,propylbutadienylene, pentenylene, hexenylene, heptenylene, hexadienyleneand heptadienylene, preferably methine, vinylene, propenylene,butenylene and butadienylene. Herein, when said carbon chain istrivalent, it binds to a carbon atom on Ring J' at any possible positionby a double bond.

Examples of the "straight-chain or branched alkylene chain" shown by Linclude straight-chain or branched C₁₋₆ alkylene chain, morespecifically, divalent ones such as methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, propylene,ethylmethylene, ethylethylene, propylethylene, butylethylene,methyltetramethylene and methyltrimethylene, and, preferably, C₁₋₃ onessuch as methylene, ethylene, trimethylene and propylene.

Among the above-exemplified groups shown by X', the groups representedby the formula (b)

    --X.sub.1 --Y

wherein X₁ is a bond or a divalent atomic chain; Y is an optionallyesterified carboxyl group, an optionally substituted carbamoyl group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup or an optionally substituted heterocyclic radical having aprotonizable hydrogen, are preferable.

In the formula (b), the "divalent atomic chains" shown by X₁ aresubstantially the same as those in the case of the above-mentioneddivalent atomic chains shown by X.

In the formulae (a) and (b), as the "divalent atomic chain" shown by Xor X₁, more preferably, mention is made of straight-chain or branchedalkylene chain, in which the carbon number constituting thestraight-chain ranges from 1 to 7 (preferably from 1 to 4). Examples ofsaid alkylene chain include divalent ones such as methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, propylene, ethylmethylene, ethylethylene,propylethylene, butylethylene, methyltetramethylene andmethyltrimethylene, and, preferably C₁₋₄ ones such as methylene,ethylene, trimethylene and propylene.

As the spacer having a chain length of 1 to 7 atoms shown by X, any onecan be exemplified, so long as it is a divalent chain in which thenumber of atoms constituting the straight chain is 1 to 7, and it mayhave a side chain.

For example, said spacer includes one represented by the followingformula: ##STR9## wherein m and n denote independently 0, 1, 2 or 3; Estands for a bond or oxygen atom, sulfur atom, sulfoxide, sulfone,##STR10## Herein, R₆ and R₇ independently stand for hydrogen atom, anoptionally substituted lower alkyl group, an optionally substitutedaralkyl group or an optionally substituted phenyl group. And, R₅ standsfor hydrogen atom, a lower alkyl group, aralkyl group or acyl group.

As the alkyl groups of "optionally substituted lower alkyl groups" shownby R₆ and R₇, mention is made of C₁₋₆ straight-chain or branched loweralkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.). As thesubstituent of said optionally substituted lower alkyl group, mention ismade of aromatic heterocyclic groups (e.g. furyl, thienyl, pyridyl,pyrimidinyl, pyrazinyl, indolyl, imidazolyl and isoindolyl), optionallysubstituted amino groups, optionally substituted hydroxyl groups,optionally substituted thiol groups, optionally esterified carboxylgroups and halogen atoms (e.g. fluorine, chlorine, bromine and iodine).As the substituent of optionally substituted amino group, optionallysubstituted hydroxyl group or optionally substituted thiol group,mention is made of lower (C₁₋₃) alkyl groups (e.g. methyl, ethyl andpropyl). As the optionally esterified carboxyl group, mention is made ofmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl,1-naphtoxycarbonyl, 2-naphtoxycarbonyl, with preference given tomethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl.

As the aralkyl groups of "optionally substituted aralkyl groups shown byR₄, R₆, and R₇, mention is made of benzyl, naphthylmethyl, phenylethyl,phenylpropyl, phenylbutyl, etc. As the substituent of said "optionallysubstituted aralkyl groups", mention is made of halogen atoms (e.g.fluorine, chlorine, bromine, iodine), C₁₋₃ alkoxy groups (e.g. methoxy,ethoxy, propoxy, etc.), hydroxyl group, amino group, carboxyl group,sulfhydryl, etc.

As the substituent of the optionally substituted phenyl group shown byR₄, R₆, and R₇, mention is made of halogen atoms (e.g. fluorine,chlorine, bromine and iodine), C₁₋₃ alkoxy groups (e.g. methoxy, ethoxy,propoxy, etc.) and C₁₋₃ alkyl groups (e.g. methyl, ethyl, propyl, etc.).

R₄ and R₆ may each be different depending on the corresponding methylenechains.

And, examples of "lower alkyl group" and "aralkyl group" shown by R₅include a C₁₋₄ lower alkyl group (e.g. methyl, ethyl, propyl, butyl,t-butyl, etc.), a C₇₋₁₅ aralkyl group (e.g. benzyl, phenethyl,phenylpropyl, phenylbutyl, naphthylmethyl, etc.).

As the acyl group shown by R₅, mention is made of lower alkanoyl groups(formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isoveleryl,pivaloyl and hexanoyl), lower alkenoyl groups (acryloyl, methacryloyl,crotonoyl and isocrotonoyl), cycloalkanecarbonyl (cyclopropanecarbonyl,cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexanecarbonyl),lower alkanesulfonyl groups (mesyl, ethanesulfonyl and propanesulfonyl),aroyl groups (benzoyl, p-toluoyl, 1-naphthoyl and 2-naphthoyl), aryllower alkanoyl groups (phenylacetyl, phenylpropionyl, hydroatropoyl andphenylbutyryl), aryl lower alkenoyl groups (cinnamoyl and atropoyl) andarenesulfonyl groups (benzenesulfonyl and p-toluenesulfonyl), amongothers.

Examples of optionally esterified carboxyl group shown by Y includelower alkoxycarbonyl groups (methoxycarbonyl, ethoxycarboxyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl and tert-pentyloxycarbonyl)and aryloxycarbonyl groups (phenoxycarbonyl, 1-naphtoxycarbonyl andbenzyloxycarbonyl).

Said lower alkoxycarbonyl groups may have 1 or more substituents at anypossible positions. Examples of such substituents include optionallysubstituted hydroxyl groups, optionally esterified carboxyl groups,optionally substituted carbamoyl groups, optionally substituted phenylgroups, optionally substituted C₃₋₆ cycloalkyl groups (e.g. cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl), lower C₁₋₃ alkenyl groups (e.g.vinyl, allyl, etc.) and 5-membered heterocyclic residue containing oneto three of oxygen atom. As the Substituent of said optionallysubstituted hydroxyl group, mention is made of lower alkanoyl groups(e.g. pivaloyl, etc.) and optionally esterified carboxyl groups (e.g.methoxycarbonyl, ethoxycarboxyl, propoxycarbonyl, isopropoxycarbonyl andcyclohexyloxycarbonyl). As the substituent of said optionally esterifiedcarboxyl group, mention is made of lower C₁₋₄ alkoxycarbonyl groups(e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl tert-butoxycarbonyl andsec-butoxycarbonyl). As the substituent of said optionally carbamoylgroup, mention is made of lower C₁₋₃ alkyl groups (e.g. methyl, ethyland propyl), C₃₋₆ cycloalkyl groups (e.g. cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), phenyl group, benzyl group and optionallyesterified carboxyl groups (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl). As the substituents of said optionally substitutedphenyl group or optionally substituted C₃₋₆ cycloalkyl group, mention ismade of lower C₁₋₃ alkyl groups (e.g. methyl, ethyl and propyl) andlower C₁₋₃ alkoxy groups (e.g. methoxy, ethoxy and propoxy). Said5-membered heterocyclic residue may have 1 or more substituents at anypossible positions. Examples of such substituents include lower C₁₋₃alkyl groups (e.g. methyl, ethyl and propyl) and oxo. Further, saidheterocyclic group may cooperate with a benzen ring to form a fusedring.

Said aryloxycarbonyl group may have 1 or more substituents at anypossible positions. Examples of such substituents include lower C₁₋₃alkyl groups (e.g. methyl, ethyl and propyl), lower C₁₋₃ alkoxy groups(e.g. methoxy, ethoxy and propoxy) and optionally esterified carboxylgroups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl).

Also, the optionally esterified carboxyl group shown by Y may bethioesterified.

Exemplary substituents of optionally substituted hydroxyl groups shownby Y include lower C₁₋₄ alkyl groups (e.g. methyl, ethyl, propyl,isopropyl, butyl and t-butyl), C₃₋₆ cycloalkyl groups (cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl), optionally substituted arylgroups (e.g. phenyl, 1-naphthyl and 2-naphthyl) and optionallysubstituted aralkyl groups (e.g. benzyl and phenethyl). As substituentsof said optionally substituted aryl groups and optionally substitutedaralkyl groups, mention is made of halogen atoms (e.g. fluorine,chlorine, bromine, iodine), and carboxyl groups optionally esterifiedwith lower (C₁₋₄) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,and t-butyl).

Exemplary substituents of optionally substituted amino groups shown by Yinclude lower C₁₋₄ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl,butyl and t-butyl), C₃₋₆ cycloalkyl groups (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), optionally substituted aryl groups (e.g.phenyl, 1-naphthyl and 2-naphthyl) and optionally substituted aralkylgroups (e.g. benzyl and phenethyl). As substituents of said optionallysubstituted aryl groups and optionally substituted aralkyl groups,mention is made of halogen atoms (e.g. fluorine, chlorine, bromine,iodine), and carboxyl groups optionally esterified with lower (C₁₋₄)alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, and t-butyl). Also,two substituents on a nitrogen atom may form a cyclic amino group takentogether with the nitrogen atom. Examples of the cyclic amino groupinclude 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino,1-piperazinyl, and 1-piperazinyl having a lower C₁₋₃ alkyl group (e.g.methyl, ethyl, propyl, etc.), an aralkyl group (e.g. benzyl, phenethyl,etc.), an aryl group (e.g. phenyl, etc.) or the like at the 4-position.

Example substituents of optionally substituted phenyl group shown by Yinclude optionally substituted lower C₁₋₄ alkyl groups (e.g. methyl,ethyl, propyl, isopropyl, butyl and t-butyl), lower C₁₋₄ alkoxy groups(e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy),optionally esterified carboxyl groups (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl and sec-butoxycarbonyl), optionally substitutedphenyl groups, optionally substituted amino groups and a N-containingheterocyclic residue having hydrogen atom capable of being deprotonated.

As the substituent of said optionally lower C₁₋₄ alkyl group or saidoptionally substituted phenyl group, mention is made of optionallyesterified carboxyl groups (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyland sec-butoxycarbonyl). As the substituent of said optionallysubstituted amino group, mention is made of lower C₁₋₃ alkyl groups(e.g. methyl, ethyl and propyl). Said N-containing heterocyclic residueincludes tetrazol-5-yl, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl.

Exemplary substituents of optionally substituted carbamoyl groups shownby Y include optionally substituted lower C₁₋₆ alkyl groups (e.g.methyl, ethyl, propyl, isopropyl, butyl, and t-butyl), optionallysubstituted C₃₋₆ cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl), optionally substituted aryl group (e.g. phenyl,1-naphthyl, 2-naphthyl, etc.), optionally substituted aralkyl groups(e.g. benzyl, phenethyl, etc.), and, one or two of these substituentsmay be independently substituted. As substituents of said optionallysubstituted lower (C₁₋₆)alkyl and optionally substituted C₃₋₆ cycloalkylgroup, mention is made of a carboxyl group optionally esterified with alower (C₁₋₅ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,t-butyl, pentyl, isopentyl, neopentyl, etc.), aromatic heterocyclicgroups (e.g. furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl,pyrimidyl, imidazolyl, etc.), amino group, hydroxyl group, phenyl group,etc., and one to three of these substituents may be independentlysubstituted. As substituents of said optionally substituted aryl groupsand optionally substituted aralkyl groups, mention is made of halogenatoms (e.g. fluorine, chlorine, bromine, iodine), carboxyl groupsoptionally esterified with a lower (C₁₋₄) alkyl (e.g. methyl, ethyl,propyl, isopropyl, butyl, t-butyl, etc.). Also, two substituents on anitrogen atom may form a cyclic amino group taken together with thenitrogen atom. Examples of such cyclic amino groups include1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl,etc.

As heterocyclic radicals of the "optionally substituted heterocyclicradical having a protonizable hydrogen" shown by Y, mention is made of5-7 membered (preferably 5-membered) monocyclic heterocyclic radicalscontaining at least one hetero atom selected from the group consistingof N, S and O, more preferably N-containing heterocyclic radicals.Especially, tetrazol-5-yl and groups represented by the formula##STR11## wherein i stands for --O-- or --S--; j stands for >C═O, >C═Sor >SO₂ (especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) are preferable.

Examples of N-containing heterocyclic residues having a hydrogen atomcapable of being protonated shown by Y also include tetrazol-5-yl,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl.

Said heterocyclic radical may be protected with an optionallysubstituted lower alkyl (preferably C₁₋₄ alkyl), acyl, etc. As saidoptionally substituted lower alkyl, mention is made of methyl,triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl,p-nitrobenzyl, etc. Examples of said acyl include lower (C₂₋₅) alkanoyl,benzoyl, etc.

As the substituent of ring A, mention is made of halogen atoms (e.g.fluorine, chlorine, bromine, iodine), C₁₋₄ optionally substituted loweralkyl groups (e.g. methyl, ethyl, propyl, butyl and tert-butyl), C₁₋₄optionally substituted lower alkoxy groups (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy and tert-butoxy), nitro group and cyanogroup. The ring A may have 1 to 3, preferably one or two, of thesesubstituents. And, these substituents may form a ring with each of theadjacent substituents. As the substituent of said optionally substitutedlower alkyl group or optionally substituted lower alkoxy group, mentionis made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine), and1 to 3 of these halogen atoms may be substituted on an optionalposition.

And, when X is shown by the formula ##STR12## wherein symbols are of thesame meaning as defined above, E is preferably a bond or --CONH--. WhenE is --CONH--, preferably m=1, n=1 or m=2, n=1, especially m=1, n=1. Inthis case, R₆ is preferably hydrogen atom benzyl and 3-indolyl methyl,especially hydrogen atom and 3-indolyl methyl. When E is --CONH--, Y ispreferably carboxyl group and esterified carboxyl group, especiallycarboxyl group.

Further, preferable examples of substituents of the ring A include nosubstituent, lower alkoxy or a halogen atom, and methoxy or chlorineatom is especially preferable.

As salts of the compound (I), (I') or (I"), mention is made ofpharmacologically acceptable salts including inorganic salts such ashydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., organicacid salts such as acetate, tartrate, citrate, fumarate, maleate,toluensulfonate, methanesulfonate, etc., metal salts such as sodiumsalt, potassium salt, calcium salt, aluminium salt, etc. and basic saltssuch as triethylamine salt, guanidine salt, ammonium salt, hydrazinesalt, quinine salt, cinchonine salt, etc.

Further, the present invention provides a method of producing a compoundrepresented by the formula (I) or the formula (I'): ##STR13## whereineach of the symbols is of the same meaning as defined above or apharmaceutically acceptable salt thereof, by subjecting a compoundrepresented by the following formula: ##STR14## wherein W is ##STR15##wherein R₈ is halogen (e.g. fluorine, chlorine, bromine and iodine) or--OSO₃ CH₃ or other symbols are of the same meaning as defined above, toa cyclization reaction.

Methods of producing compounds of this invention are described below:

Among the compounds of formula (I) and (I'), compounds represented bythe formula (Ia) ##STR16## wherein R₄ stands for a C₁₋₈ alkyl group oraralkyl group, and other symbols are of the same meaning as definedabove, can be produced by the following methods.

2-aminobenzophenones as the starting material can be synthesized by, orin accordance with, the method described in D. A. Walsh, Synthesis, 677(1980) or the method cited in said reference.

Among the above-exemplified groups shown by X', an alkyl groupsubstituted with an optionally esterified carboxyl group or an alkylgroup substituted with an optionally substituted heterocyclic radicalhaving a protonizable hydrogen are preferable.

In the formulae (Ir), as aromatic heterocyclic rings shown by ring A,mention is made of aromatic heterocyclic groups described in detailreferring to R₁. Among them, groups represented by the formulae##STR17## are preferable.

As substituents of the "optionally substituted benzene rings" and"optionally substituted aromatic heterocyclic groups" shown by ring A,mention is made of halogen (e.g. fluorine, chlorine, bromine, iodine),C₁₋₄ optionally substituted lower alkyl groups (e.g. methyl, ethyl,propyl, butyl, tert-butyl, etc.), C₁₋₄ optionally substituted loweralkoxy groups (methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, etc.), hydroxy, nitro group, cyano, etc. the ring A mayhave 1 to 3 of these substituents, preferably 1 to 2. And, thesesubstituents may form a ring, taken together with respectively adjacentsubstituents. As substituents of said optionally substituted lower alkylgroups or those of optionally substituted lower alkoxy groups, mentionis made of halogen atoms (e.g. fluorine, chlorine, bromine, iodine),etc., which may have 1 to 3 substituents at optional positions. As ringsA, those which are substituted with methoxy or chlorine atom arepreferable, especially those substituted with chlorine are preferable.

In the formula (Ir'), as substituents of the "optionally substitutedbenzene rings" shown by ring B, mention is made of halogen (e.g.fluorine, chlorine, bromine, iodine), C₁₋₄ optionally substituted loweralkyl groups (e.g. methyl, ethyl, propyl, butyl, tert-butyl, etc.), C₁₋₄optionally substituted lower alkoxy groups (methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, etc.), hydroxy, nitro group, cyano,etc. the ring B may have 1 to 3 of these substituents, preferably 1 to2. And, these substituents may form a ring, taken together withrespectively adjacent substituents. As substituents of said optionallysubstituted lower alkyl groups or those of optionally substituted loweralkoxy groups, mention is made of halogen atoms (e.g. fluorine,chlorine, bromine, iodine), etc., which may have 1 to 3 substituents atoptional positions. As rings B, those which are substituted with methoxyor chlorine atom are preferable, especially those substituted withchlorine are preferable.

In the formula (Ir), as heterocyclic rings of the "7- or 8-memberedheterocyclic ring containing at most three ring constituting heteroatoms" shown by ring J', mention is made of saturated or unsaturated 7-or 8-membered heterocyclic rings containing, as the atoms constitutingthe cyclic ring, at least one hetero-atom selected from O, S(O)_(q) (qis 0, 1 or 2) and N, provided that the number of hetero atoms in theatoms constituting the cyclic system (ring constituting atoms) of saidheterocyclic ring is at most three.

And, the ring J' may optionally have, besides the groups represented byR₁, R₂, R₃ and X', one or two appropriate substituents at any possibleposition. As said substituent, when it binds to a nitrogen atom on thering J', mention is made of C₁₋₆ straight-chain or branched alkyl groups(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, neopentyl, etc.), acyl groups such as C₁₋₄ acylgroups (e.g. formyl, acetyl, propionyl, butyroyl, etc.), etc. Said alkylor said acyl may have one to five of halogen atoms (e.g. fluorine,chlorine, bromine, iodine). And, when said substituent binds to a carbonatom or the ring J', mention is made of oxo, thioxo, an optionallysubstituted hydroxyl group, an optionally substituted amino group, etc.Said optionally substituted hydroxyl group and said optionallysubstituted amino group are substantially the same as the "optionallysubstituted hydroxyl group and the "optionally substituted amino groupshown by Y.

The ring J' is preferably substituted with oxo or thioxo, besides thegroups of R₁, R₂, R₃ and X', at any possible position.

As the condensed ring composed of Ring A and Ring J', mention is made of##STR18##

The formula (Ir)is preferably one represented by the formula (Ir_(a)):##STR19## wherein R₁, R₂, R₃, X' and Ring A are of the same meaning asdefined above; Ring J₁ is a 7-membered heterocyclic ring; Z₁ is ═N--,--N(R₇)-- (wherein R₇ is hydrogen, alkyl group or acyl group), --(O)_(q)-- (wherein q is 0, 1 or 2), --CH₂ -- or --O--; K is C or N; G is O orS; the symbol ......... is a double bond when Z₁ is ═N--, while a singlebond when Z₁ is not ═N--.

In the formula (Ir_(a)), as alkyl groups shown by R₇, mention is made ofC₁₋₆ straight-chain or branched lower alkyl groups (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, etc.), which may optionally be substituted with 1 to 5halogen atoms (e.g. fluorine, chlorine, bromine, iodine).

As acyl groups shown by R₇, mention is made of C₁₋₄ acyl groups (e.g.formyl, acetyl, propionyl, butyroyl, etc.), which may optionally besubstituted with 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine,iodine).

The formula (Ir_(a)) is preferably one represented by the formula(Ir_(b)): ##STR20## wherein R₁, R₂, R₃, X₁, Y and Ring A are of the samemeaning as defined above; Z₂ is S(O)_(q) -- (wherein q is 0, 1 or 2) orO.

The formula (Ir)is more preferably one represented by the formula (Ir").##STR21## wherein R₁ and Ring B are of the same meaning as definedabove; Q is hydrogen or a metal ion; ring C is an optionally substitutedphenyl group. Here, the formula (Ir") shows a trans-isomer in which thesubstituents at 3- and 5-positions are oriented in the adversedirections to each other relative to the face of 7-membered ring. And(R) shows (R)-configuration.

In the formula (Ir"), as the metal ion shown by Q, mention is made ofsodium salt, potassium salt, calcium salt and aluminium salt, etc,preferably sodium salt, potassium salt.

Examples of the "optionally substituted phenyl group" shown by ring Care substantially the same as those in the case of the above-mentioned"optionally substituted phenyl group" shown by R₂ and R₃.

The compounds in this invention are specifically disclosed as follows:

(3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-cyano-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chlorophenyl)-2,3,4,5-tetrahydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-aceticacid,

N-(3R,5S)-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!glycine,

(3R,5S)-7-Chloro-5-(2-chlorophenyl)-3-dimethylaminocarbonylmethyl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine,

7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H-1!-benzazepine-3-acetic acid,

(3R,5S)-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,1-benzoxazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno2,3-e!oxazepine-3-acetic acid,

(3R,5S)-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno2,3-e!oxazepine-3-acetic acid,

(3R,5S)-7-Chloro-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno2,3-e!oxazepine-3-acetic acid,

(3R,5S)-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-3-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-4-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-3-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-chloro-5-(2-chloro-4-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-3-hydroxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-4-hydroxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-3-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid,

(3R,5S)-7-Chloro-5-(2-chloro-4-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-aceticacid, etc.

As salts of the compounds (Ir), (Ir_(a)), (Ir_(b)), (Ir') and (Ir"),mention is made of, pharmaceutically acceptable ones, for example,inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate,phosphate, etc.; organic acid salts such as acetate, tartrate, citrate,fumarate, maleate, toluenesulfonate, methanesulfonate, etc.; metal saltssuch as sodium salt, potassium salt, calcium salt, aluminum salt, etc.,and salts with a base such as triethylamine salt, guanidine salt,ammonium salt, hydrazine salt, quinine salt, cinchonine salt, etc.

The compounds (Ir), (Ir_(a)), (Ir_(b)), (Ir') and (Ir") were, forinstance, disclosed in EP567026, U.S. application Ser. No. 08/195,131filed Feb. 9, 1994 and Japanese patent application Nos. 6-15531/1994,6-229159/1994 and 6-229160/1994, and can be produced as described inthese publications.

The compounds represented by the formula (Ir), (Ir_(a)), (Ir_(b)), (Ir')and (Ir") in this invention have a hypotriglyceridemic activity, whichis useful for the prophylaxis or therapy of hyperlipidemia of mammals(e.g. mouse, rat, rabbit, dog, cat, cow, pig and human being), and arealso useful for the treatment and prevention of renal failure such asnephritis and nephrosis, atherosclerosis, ischemic heart disease,myocardial infarction, angina pectoris, aneurysm, cerebroslerosis,peripheralsclerosis, thrombosis, diabetes (for example type based oninsulin resistance), pancreatitis and restenosis after PTCA.

The compounds represented by the formulae (Ir), (Ir_(a)), (Ir_(b)),(Ir') and (Ir") are useful for the treatment and prevention ofhyperlipidemia with increased triglyceride level, such ashypertriglyceridemia.

Compound (Ir), (Ir_(a)), (Ir_(b)), (Ir') and (Ir") or salts thereof canbe administered by the oral route, non-oral route, inhalation, rectalinjection, or topical administration, as pharmaceutical constituents orpreparations (e.g., powder, granules, tablets, pills, capsules,injection, syrup, emulsion, elixir, suspension, solution, etc.). Atleast one compound of the present invention can be used singly or inmixture with a carrier allowable as a pharmaceutical (adjuvant, vehicle,supportive agent, and/or diluting agent).

The constituents of a pharmaceutical can be prepared according to theusual manner. In the present specification, the non-oral route includessubcutaneous injection, intravenous injection, intramuscular injection,peritoneal injection and intravenous drip. For prescription injection,sterile aqueous or oily suspensions for injection can be prepared byusing an appropriate emulsifier or humidifier and a suspending agent,according to known methods. The sterile prescription agent for injectionmay be a non-toxic, non-orally administrable diluting agent such asaqueous solution or a sterile injectable solution or suspension in asolvent. As the usable vehicle or solvent, water, Ringer's solution,isotonic saline, etc. are allowed; as an ordinary solvent, or suspendingsolvent, sterile involatiole oil can be used. For these purposes, anykind of involatile oil and fatty acid can be used, including natural orsynthetic or semisynthetic fatty oils or fatty acids; natural orsynthetic or semisynthetic mono- or di- or tri-glycerides.

The suppository for rectal administration can be manufactured via aparticular process, in which the drug is mixed with an appropriate,non-irritant supporting agent, e.g., cocoa butter or polyethyleneglycol, that is solid at normal temperature but liquid at intestinaltemperature and therefore melts in the rectum to release the drug.

As the solid-type dosage form for oral administration, powder, granules,tablets, pills and capsules are listed as mentioned above. In thesedosage forms, the active constituent compound can be mixed with at leastone additive, including sucrose, lactose, cellulose, mannitol, maltitol,dextran, starches, agar, arginates, chitins, chitosans, pectins, gumtragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic orsemisynthetic polymer, and glyceride. These dosage forms can alsocontain other type(s) of additives, e.g., inactive diluting agent,lubricant such as magnesium stearate, paraben, preserving agent such assorbic acid, ascorbic acid, α-tocopherol, antioxidant such as cysteine,disintegrator, binder, thickener, buffering agent, sweetening agent,flavoring agent, perfuming agent, etc. Tablets and pills can be furtherprocessed into enteric coated preparations. The liquid preparations fororal administration include emulsion, syrup, elixir, suspension andsolution preparations allowable for medical use. These preparations maycontain inactive diluting agents ordinarily used in said field, e.g.,water.

The dosage for a particular patient is determined according to age, bodyweight, general health conditions, sex, diet, administration time,administration method, excretion rate, drug combination, and severity ofthe illness being treated, in consideration of those or other factors.

The compounds (Ir), (Ir_(a)), (Ir_(b)), (Ir') and (Ir") or salts thereofare low in toxicity and can be used safely. While the daily dosagevaries with the conditions or body weight of the subject patient, kindsof the compounds, administration route, etc., in the case ofadministering the compound in the present invention for the therapy ofhyperlipidemia, a daily oral dosage per adult human is about 1 to 500mg, preferably about 10 to 200 mg, while a daily non-oral dosage peradult human is about 0.1 to 100 mg, preferably about 1 to 50 mg. Withinthis range, no toxicity is observed at all.

EXAMPLES!

The following examples are intended to illustrate the present inventionin further detail and should by no means be construed as defining themetes and bounds of the invention.

Formulation Examples

A hypotriglyceridemic agent containing, as its effective component, acompound represented by the formula (Ir), (Ir_(a)), (Ir_(b)), (Ir')and(Ir") of this invention or a salt thereof, can be formulated inaccordance with, for example, the following prescriptions.

1. Capsules

(1) Sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) are blended and the mixture isgranulated, to which was added the balance of (4). The mixture is filledin a gelatin capsule.

2. Tablets

(1) Sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) are blendedand the mixture is granulated, to which are added the balance of (4) and(5). The mixture is subjected to compression-molding to provide tablets.

3. Injections

(1) Sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Inositol 100 mg

(3) Benzyl alcohol 20 mg

One ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is put in an ampoule, and the ampoule issealed. All the processes are conducted under sterilized conditions.

4. Capsules

(1) Sodium(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) are blended and the mixture isgranulated, to which is added the balance of (4). The mixture is filledin a gelatin capsule.

5. Tablets

(1) Sodium(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) are blendedand the mixture is granulated, to which are added the balance of (4) and(5). The mixture is subjected to compression-molding to provide tablets.

6. Injections

(1) Sodium(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Inositol 100 mg

(3) Benzyl alcohol 20 mg

One ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is put in an ampoule, and the ampoule issealed. All the processes are conducted under sterilized conditions.

7. Capsules

(1) Sodium(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) are blended and the mixture isgranulated, to which is added the balance of (4). The mixture is filledin a gelatin capsule.

8. Tablets

(1) Sodium(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) are blendedand the mixture is granulated, to which are added the balance of (4) and(5). The mixture is subjected to compression-molding to provide tablets.

9. Injections

(1) Sodium(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate10 mg

(2) Inositol 100 mg

(3) Benzyl alcohol 20 mg

One ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is put in an ampoule, and the ampoule issealed. All the processes are conducted under sterilized conditions.

10. Capsules

(1)(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid 10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) are blended and the mixture isgranulated, to which is added the balance of (4). The mixture is filledin a gelatin capsule.

11. Tablets

(1)(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid 10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) are blendedand the mixture is granulated, to which are added the balance of (4) and(5). The mixture is subjected to compression-molding to provide tablets.

12. Capsules

(1)(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid 10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) are blended and the mixture isgranulated, to which is added the balance of (4). The mixture is filledin a gelatin capsule.

13. Tablets

(1)(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid 10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) are blendedand the mixture is granulated, to which are added the balance of (4) and(5). The mixture is subjected to compression-molding to provide tablets.

14. Capsules

(1)(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid 10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) are blended and the mixture isgranulated, to which is added the balance of (4). The mixture is filledin a gelatin capsule.

15. Tablets

(1)(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid 10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) are blendedand the mixture is granulated, to which are added the balance of (4) and(5). The mixture is subjected to compression-molding to provide tablets.

TEST EXAMPLES

Bioactivity of the compounds (Ir), (Ir_(a)), (Ir_(b)), (Ir') and (Ir"),or salts thereof are described by means of the following test examples.

Examples 1

Plasma lipid lowering effects in marmosets.

Method!

Male common marmosets (19-68 months old, purchased from Japan EDM Co.,Ltd.) were given sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(test compound A), sodium(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(test compound B) or sodium(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(test compound C) solution by stomach tube for 4 days. Blood was takenfrom femoral vein of non-fasted animals and plasma total cholesterol,HDL-cholesterol and triglyceride were measured enzymatically usingcommercially available kits (Wako Pure Chemical Industries, Ltd. forcholesterol and Iatron Laboratories, Inc. for triglyceride). Non-HDLcholesterol was calculated by subtracting HDL-cholesterol from totalcholesterol.

Results!

Results were shown in Table 1.

                  TABLE 1    ______________________________________    Plasma lipid lowering effects in marmosets    Test    compound A               B         C    ______________________________________    Dose     10        50        50      50    (mg/kg/day)    Number of              6         5         6       6    animal    Total    18 ± 9*                       21 ± 16*                                 21 ± 5*                                         3 ± 3    cholesterol    Non-HDL- 34 ± 8*                       53 ± 9*                                 25 ± 11*                                         27 ± 11*    cholesterol    Triglyceride              25 ± 13*                       56 ± 16*                                 64 ± 10*                                         44 ± 17*    ______________________________________

Initial plasma levels were 169±29 mg/dl for total cholesterol, 98±19mg/dl for non-HDL cholesterol and 253±177 mg/dl for triglyceride. Valuesrepresent percent reduction from the initial value. Mean±SD. *p<0.05 vsthe initial value by Student's paired t-test.

Plasma total cholesterol, non-HDL cholesterol and triglyceride weresignificantly reduced by the administration of these compounds in commonmarmosets. Lipid lowering effects of compound A were dose-dependent.

Example 2

Plasma lipid lowering effects in Wistar fatty rats

Method!

Thirty-week-old, male wistar fatty rats (Ikeda, H., Shino, A., Matsuo,T., Iwatsuka, H. and Suzuoki, Z. Diabetes 1981, 30:1045) were given a0.5%-methylcellulose solution of sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(test compound) was given by stomach tube for 2 weeks. Blood was takenfrom orbital sinus of non-fasted animals and plasma total cholesterol,HDL-cholesterol and triglyceride were measured enzymatically usingcommercially available kits (Wako Pure Chemical Co. Ltd. for cholesteroland Iatron Laboratories, Inc. for triglyceride). Non-HDL cholesterol wascalculated by subtracting HDL-cholesterol from total cholesterol.

Results!

Results were shown in Table 2.

                  TABLE 2    ______________________________________    Plasma lipid lowering effects in Wistar fatty    rats             Control   Test compound    ______________________________________    Dose (mg/kg/d)               0           10        30    Number of  6            6         6    animal    Total      186 ± 15.sup.a                           173 ± 17.sup.ab                                     160 ± 25.sup.b    cholesterol    (mg/dl)    Non-HDl    77.8 ± 6.3.sup.a                           70.8 ± 11.6.sup.a                                     52.6 ± 9.2.sup.b    cholesterol    (mg/dl)    Triglyceride               353 ± 68.sup.a                           295 ± 49.sup.a                                     230 ± 30.sup.b    (mg/dl)    ______________________________________

Values represent mean ± SD. Different superscripts in the same rowrepresent a significant difference (p<0.05) by Duncan's multiple rangetest.

Plasma total cholesterol, non-HDL cholesterol and triglyceride weresignificantly and dose-dependently reduced by the administration of thecompound in Wistar fatty rats. ##STR22## wherein Z stands for a halogenatom, and other symbols are of the same meaning as defined above.

The reactions from the formula (II) to the formula (IV) and from theformula (VIII) to the formula (IX) in the above-mentioned Method A! orthose from the formula (X) to the formula (XI) and from the formula(XIV) to the formula (XII) in the above-mentioned Method B! can becarried out by utilizing a per se known acylation reaction. For example,the acylation reaction of this invention can be conducted in a solventexemplified by an ether-type solvent such as diethyl ether,tetrahydrofuran, dioxane, etc., a halogen-type solvent such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.,a hydrocarbon-type solvent such as benzene, toluene, hexane, heptane,etc., dimethylformamide, dimethyl sulfoxide, etc., and, depending onnecessity, in the presence of water and a base (e.g. an organic basesuch as 4-dimethylaminopyridine, triethylamine, triethylenediamine,tetramethylethylenediamine, etc. an inorganic base such as sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, etc, sodiumhydride, potassium hydride), among others. Relative to one mole of acompound represented by the formulae (II), (VIII), (X) and (XIV), acidchloride and methanesulfonyl chloride by the formula (III) and ester of4-chloroformyl butyric acid are usually employed in an amount of 1 to 10mol., preferably 1 to 3 mol. And, the reaction time usually ranges fromabout 1 to 48 hours, preferably from about 5 to 10 hours. The reactiontemperature ranges from -50° to 100° C., preferably from about 0° to 50°C.

And, the reaction from the formula (IV) to the formula (VI) in Method A!and the reactions from the formula (II) to the formula (X) and from theformula (XIII) to the formula (XIV) in Method B! can be carried out inan ether type solvent such as diethyl ether, tetrahydrofuran, dioxaneetc., a hydrocarbon type solvent such as benzene, toluene, hexane,heptane etc., an alcohol type solvent such as methanol, ethanol,propanol, butanol etc., acetone or dimethylformamide, and, depending onnecessity, in the presence of a base (e.g. sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate,sodium hydride, potassium hydride or the like). Relative to one mole ofa compound represented by the formula (II), the formula (IV) or theformula (XIII), a compound represented by the formula (V) is employedusually in an amount ranging from 1 to 10 mol., preferably about 1 to 2mol. The reaction temperature ranges from 0° to 100° C., preferably fromabout 20° to 50° C. The reaction time ranges usually from 1 to 24 hours,preferably about 3 to 10 hours.

And, the reduction reaction of carbonyl group from the formula (IX) tothe formula (Ia') in Method A!, from the formula (II) to the formula(XIII) and from the formula (XI) to the formula (XII) in Method B! canbe conducted in a protonic solvent (e.g. methanol, ethanol, propanol,butanol, etc.) or a non-protonic solvent (e.g. ethyl ether,tetrahydrofuran, dioxane, etc.) in the presence of a metal hydrogencomplex (e.g. lithium aluminum hydride, sodium aluminum hydride, sodiumtriethoxyaluminium hydride, sodium borohydride, etc.). Relative to oneeach mol. of compounds shown by the formula (IX), the formula (II) andthe formula (XI), such a metal hydrogen complex as mentioned above isemployed in an amount, usually ranging from 0.3 to 5 mol. equivalents,preferable from 0.5 to 2 mol. equivalents. The reaction temperatureranges from -20° to 100° C., preferably from 20° to 50° C.

The cyclization reaction to the formula (Ia') from the formula (XII) inMethod B! can be carried out in a solvent, for example, an ether typesolvent such as diethyl ether, tetrahydrofuran, dioxane, etc., ahydrocarbon type solvent such as benzene, toluene, hexane, heptane,etc., an alcohol type solvent such as methanol, ethanol, propanol,butanol, etc., acetone, dimethylformamide or the like, in the presenceof, depending on necessity, a base (e.g. sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate,sodium hydride, potassium hydride, etc.). Relative to one mol. of acompound shown by the formula (XII), a base as exemplified above isemployed in an amount usually ranging from 1 to 5 mol., preferable fromabout 1 to 2 mol. The reaction temperature ranges usually from -20° to200° C., preferably from 20° to 100° C. The reaction time ranges usuallyfrom 1 to 20 hours, preferably from 2 to 5 hours.

The reaction from the formula (VI) to (VIII) in Method A! can beconducted in an alcohol shown by the formula (VII), and, depending onnecessity, in the presence of an inorganic acid such as nitric acid,hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acidsuch as toluenesulfonic acid or methanesulfonic acid, at temperaturesranging from -20° to 100° C., preferably from 20° to 50° C. The reactiontime ranges from 10 to 100 hours, preferably from 10 to 48 hours.

The compound shown by the formula (Ia") can be produced in accordancewith a conventional method.

Among the compounds shown by the formula (I) and (I'), a compoundrepresented by the formula (Ib) ##STR23## wherein symbols are of thesame meaning as defined above, can be produced by subjecting a compoundshown by the formula (Ia) to hydrolysis, for example, by processing acompound shown by the formula (Ia) with an acid or a base. Morespecifically, a compound shown by the formula (Ia) is processed in anaqueous solution of a mineral acid (e.g. nitric acid, hydrochloric acid,hydrobromic acid, iodic acid, sulfuric acid or the like) or an alkalimetal hydroxide (sodium hydroxide, potassium hydroxide, bariumhydroxide, lithium hydroxide) at temperatures ranging from 0° to 150°C., preferably from 20° to 50° C. The strength of the acid or the baseranges usually from 1 to 10N, preferably from 4 to 10N. The reactiontime varies with the reaction temperature, but usually ranges from 1 to24 hours, preferably from about 2 to 10 hours.

A compound shown by the formula (Ib') ##STR24## wherein symbols are ofthe same meaning as defined above, can be produced by subjecting acompound shown by the formula (Ic') ##STR25## wherein symbols are of thesame meaning as defined above, to oxidation. The solvent then to be usedmay be any one so long as it does not hamper the reaction, which isexemplified by acetone, dioxane, tetrahydrofuran, dichloromethane,dichloroethane or chloroform. As the oxidizing agent, permanganate,chromic acid or nickel peroxide can be used, for example. In this case,the oxidizing agent is used in an amount ranging from 0.5 to 20 mol.equivalents, preferably from 1 to 3 mol. equivalents, relative to onemol. of the compound shown by the formula (Ic'), the reactiontemperature ranges from 0° to 100° C., preferably from 15° to 50° C. andthe reaction time ranges from 0.5 to 5 hours, preferably from about 1 to2 hours.

Among the compounds to be used as intermediates for synthesizing acompound of formula (I) or (I'), a compound shown by the formula (XIX)##STR26## wherein symbols are of the same meaning as defined above, canbe produced by allowing a compound shown by the formula (Ib) to reactwith diphenylphosphoryl azide in a solvent in the presence of a base,then by processing the resultant with an acid in a solvent. The solventto be used in the reaction between a compound shown by the formula (Ib)and diphenylphosphoryl azide may be any one, so long as it does nothamper the reaction, which is exemplified by dimethylformamide, ahalogen-type solvent such as dichloromethane, chloroform ordichloroethane and an ether-type solvent such as ether, tetrahydrofuranor dioxane. Typical examples of the base to be employed includetriethylamine, 4-dimethylaminopyridine, triethylenediamine andtetramethylethylenediamine. Relative to 1 mol. of a compound shown bythe formula (Ib), 1 to 10 mol. equivalents, preferably about 1.5 to 3mol. equivalents, of diphenylphosphoryl azide is employed. The reactiontemperature ranges from -20° to 50° C., preferably from 0° to 20° C.,and the reaction time ranges from 0.5 to 5 hours, preferably from about1 to 2 hours.

In the case of processing the product obtained by the above-describedreactions, the solvent to be used is exemplified by water, dioxane,dimethylformamide etc., and, as the acid to be employed, a mineral acidsuch as sulfuric acid, hydrochloric acid, nitric acid or hydrobromicacid can be exemplified. The reaction temperature ranges from 20° to200° C., preferably from about 50° to 100° C., and the reaction timeranges from 0.5 to 5 hours, preferably from about 1 to 2 hours.

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (Ic) ##STR27## wherein symbols are of the samemeaning as defined above, can be produced by subjecting a compound shownby the formula (Ia) to reduction. More specifically, the compound shownby the formula (Ic) can be produced by processing the compound shown bythe formula (Ia) with a metal hydride complex (e.g. lithium aluminumhydride, sodium aluminum hydride, sodium borohydride) in a protonicsolvent (e.g. methanol, ethanol propanol, butanol etc.) or anon-protonic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane etc.)Relative to one mol. of the compound shown by the formula (Ia), such ametal hydride complex compound is used in an amount ranging usually from0.3 to 5 mol. equivalents, preferably from 0.5 to 2 mol. equivalents.The reaction temperature ranges from -20° C. to 100° C., preferably from0° to 20° C. The reaction time ranges from 0.5 to 10 hours, preferablyfrom about 1 to 3 hours.

And, a compound shown by the formula (Ic) can be produced also byconverting the amine portion of a compound shown by the formula (XIX)into hydroxyl group. For example, a compound of the formula (Ic) can beproduced by adding sodium nitrite to a compound of the formula (XIX) ina solvent in the presence of an acid then by processing the resultantazide compound in a solvent in the presence of a base. In the method ofazidation, for example, 0.5 to 3, preferably 1 to 1.5, mol. equivalentsof sodium nitrite, is employed relative to 1 mol. of a compound of(XIX). As the acid, any one can be employed so long as it does nothamper the reaction, typically exemplified by acetic acid and sulfuricacid. The reaction temperature ranges form -20° to 20° C., preferably 0°to 5° C., and the reaction time ranges from 5 to 60 minutes, preferablyabout 10 to 30 minutes. The method of converting the azide ofthus-obtained azide compound into hydroxyl group comprises, for example,use of, as the base, for example, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide or the like in water or an aqueousorganic solvent (e.g. an alcohol-type solvent such as methanol, ethanol,propanol, butanol or the like, an ether-type solvent such astetrahydrofuran, dioxane or the like, dimethylformamide, etc.). Thereaction temperature ranges from 20° to 200° C., preferably from 50° to100° C., and the reaction time ranges from 5 minutes to 2 hours,preferably from about 15 to 30 minutes.

The compound shown by the formula (XX) ##STR28## wherein Z' stands forhalogen (chlorine, bromine, iodine) and other symbols are of the samemeaning as defined above, which is an intermediate for synthesizing thecompound of the formula (I), can be produced by, like the methodemployed in the case of producing the compound (Ic) from the compound(XIX), subjecting a compound shown by the formula (XIX) to diazotizationwith sodium nitrite in hydrochloric acid, hydrobromic acid or hydroiodicacid, then by heating thus diazotized compound. The reaction temperatureranges from 20° to 200° C., preferably form 50° to 100° C., and thereaction time ranges from 5 minutes to 2 hours, preferably from about 15to 30 minutes.

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (Id) ##STR29## wherein Y' stands for, among thedefinitions given to Y as above, esterified carboxyl group and hydroxylgroup, and other symbols are of the same meaning as defined above, canbe produced by subjecting a compound shown by the formula (Ib) tocondensation with a compound represented by the formula (XXI) ##STR30##wherein symbols are of the same meaning as defined above, morespecifically, the compound (Ib) and the compound (XXI) are subjected tocondensation in a solvent by using a condensing agent, and, uponnecessity, in the presence of a base. The solvents to be employed areexemplified by hydrocarbon-type solvents such as benzene, toluene,hexane, heptane etc., halogen-type solvents such as dichloromethane,dichloroethane, chloroform carbon tetrachloride etc., ether-typesolvents such as ethyl ether, tetrahydrofuran, dioxane, etc.,acetonitrile, dimethylformamide, etc. As the base, use is made of, amongothers, triethylamine, 4-dimethyl aminopyridine, triethylenediamine andtetramethyl ethylenediamine. As condensing agents, mention is made ofthose to be employed for peptide synthesis, which are exemplified by,among others, cyclohexyl carbodiimide, diethyl cyanophosphate and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Relative to one mol. ofthe compound shown by the formula (Ib), a compound represented by theformula (XXI) is used in an amount ranging from 0.5 to 2 mol.equivalents, preferably from 1 to 1.2 mol. equivalent, and a condensingagent is used in an amount ranging from 0.5 to 5 mol. equivalents,preferably 1 to 2 mol. equivalents. The reaction temperature ranges from0° to 100° C., preferably from 20° to 50° C., and the reaction timeranges from 0.5 to 24 hours, preferably from about 1 to 5 hours.

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (Ie) ##STR31## wherein symbols are of the samemeaning as defined above, can be produced by allowing a compound (Ib) toreact with diphenyl phosphoryl azide in a solvent in the presence of abase, then by allowing the resultant compound to react with a compound(XXI). As the solvent to be employed in the reaction between thecompound (Ib) and diphenyl phosphoryl azide, any one can be used so longas it does not hamper the reactions which is exemplified bydimethylformamide or a halogen-type solvent such as dichloromethane,chloroform, dichloroethane etc., and an ether-type solvent such asether, tetrahydrofuran, dioxane etc. The base to be employed istypically exemplified by triethylamine, 4-dimethyl aminopyridine,triethylene diamine or tetramethyl ethylenediamine. Relative to one mol.of the compound shown by the formula (Ib), 1-10, preferably about 1.5 to3 mol. equivalents of diphenyl phosphoryl azide is employed. Thereaction temperature ranges from -20° to 50° C., preferably from 0° to20° C., and the reaction time ranges from 0.5 to 5 hours, preferablyfrom about 1 to 2 hours.

The solvent to be employed in the reaction between the compound obtainedthus above and a compound shown by the formula (XXI) is exemplified by ahalogen-type solvent such as dichloromethane, dichloroethane, chloroformetc., an ether-type solvent such as ether, tetrahydrofuran, dioxaneetc., acetonitrile, dimethylformamide, among others. And, depending onnecessity, a base is employed. As the base, mentioned is made of anorganic base including triethylamine, 4-dimethyl aminopyridine,triethylenediamine and tetramethyl ethylenediamine. Relative to one mol.of the compound (Ib), 0.5 to 3, preferably 1 to 1.5, mol. equivalents ofthe compound (XXI). The reaction temperature ranges from 0° to 150° C.,preferably from 30° to 100° C., and the reaction time ranges from 0.5 to24, preferably about 1 to 3, hours.

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (If) ##STR32## wherein symbols are of the samemeaning as defined above, can be produced by subjecting a compound of(XIX) to condensation with a compound represented by the formula (XXII)##STR33## wherein symbols are of the same meaning as defined above. Thisreaction can be conducted in completely the same manner as in theproduction of the compound (Id).

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (Ig) ##STR34## wherein E' stands for, among thedefinitions given above,oxygen atom or --NH--, and other symbols are ofthe same meaning as defined above, can be produced by allowing acompound shown by the formula (Ic) or a compound shown by the formula(XIX) to react with a compound represented by the formula (XXIII)##STR35## wherein symbols are of the same meaning as defined above. Morespecifically, the compound (Ic) or the compound (XIX) is allowed toreact with the compound (XXIII) in an alcohol-type solvent such asmethanol, ethanol, propanol, butanol etc., an ether-type solvent such asdiethyl ether, tetrahydrofuran, dioxane etc. or dimethylformamide, amongothers, in the presence of a base including an inorganic base such assodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate etc., an organic base such as triethylamine,4-dimethyl aminopyridine, triethylenediamine, tetramethylethylenediamine etc. or sodium hydride. Relative to one mol. of thecompound (Ic) or (XIX), 0.5 to 1.5 mol. equivalent of the compound(XXIII) is used, and, relative to one mol. of the compound (Ic) or(XIX), 1 to 5, preferably 1 to 2, mol. equivalents of the base is used.The reaction temperature ranges from 0° to 200° C., preferably from 20°to 100° C., and the reaction time ranges from 0.5 to 24 hours,preferably from about 1 to 3 hours.

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (Ih) ##STR36## wherein symbols are of the samemeaning as defined above, can be produced by allowing a compound (XX) toreact with a compound represented by the formula (XXV) ##STR37## whereinsymbols are of the same meaning as defined above. The solvent to beemployed is a non-protonic solvent exemplified by ethyl ether,tetrahydrofuran, dioxane, acetonitrile, dimethylformamide or the like.Depending on necessity, an inorganic base such as sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate orpotassium carbonate, an organic base such as triethylamine, 4-dimethylaminopyridine, triethylenediamine or tetramethyl ethylenediamine, sodiumhydride, cesium fluoride or the like may be used. Relative to one mol.of the compound (XX), 0.5 to 5, preferably 1 to 2, mol. equivalents ofthe compound (XXV) is employed. The reaction temperature ranges from 0°to 200° C., preferably 20° to 100° C., and the reaction time ranges from10 minutes to 5 hours, preferably from about 30 minutes to 2 hours.

Among the compounds represented by the formula (I) and (I'), a compoundshown by the formula (Ii) ##STR38## wherein symbols are of the samemeaning as defined above, can be produced by subjecting a compoundrepresented by the formula (Ij) ##STR39## wherein Y' stands for, amongthe groups defined by Y as above, esterified carboxyl group, and othersymbols are of the same meaning as defined above, to hydrolysis. Morespecifically, the hydrolysis is conducted in a solvent such as water,methanol, ethanol, propanol or butanol in the presence of an alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, bariumhydroxide or lithium hydroxide), sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate or potassium carbonate, or, in thepresence of a mineral acid (e.g. nitric acid, hydrochloric acid,hydrobromic acid, iodic acid or sulfuric acid) or trifluoroacetic acid,at temperatures ranging from 10° to 150° C., preferably from 10° to 50°C. While the reaction time varies with the reaction temperature, itranges usually from 1 to 24 hours, preferably from about 2 to 10 hours.

While the compound represented by the formula (I") of this invention hasa squalene synthetase inhibiting action and an antifungal action, amongthe compounds used in the present invention, there are compounds capableof inhibiting other enzymes in the pathway of cholesterol biosynthesis.In any event, the compound represented by the formula (I") of thisinvention inhibits biosynthesis of cholesterol, which is useful for theprophylaxis or therapy of hypercholesteremia or coronary sclerosis ofmammals (e.g. mouse, rat, rabbit, dog, cat, cow, pig and human being)and, further, for the prophylaxis or therapy of fungus infections.

Said compound (I") can be administered to man orally or non-orally. Theorally administrable compositions may be in a solid or liquid form, morespecifically tablets (including sugar-coated tablets and film-coatedtablets), syrups, emulsions, suspensions or the like. These compositionscan be prepared by a per se known method and contain carriers orexcipients conventionally used in the field of pharmaceuticalpreparation, for example, carriers or excipients such as lactose,starch, sucrose or magnesium stearate for preparing tablets.

The non-orally administrable compositions are exemplified by injectionsand suppositories, and the injections include hypodermic injections,intradermal injections and intramuscular injections. These injectionscan be prepared by a Per se known method, more specifically, bysuspending or emulsifying the compound of this invention in a sterilewater or oil conventionally used for preparing injectable compositions.The aqueous liquid to be used for preparation of injections includephysiological saline solution and isotonic solution, and, depending onnecessity, a suitable suspending agent such as sodium carboxymethylcellulose, a non-ionic surfactant or the like may be jointly used. Asthe oil, mention is made of sesame oil, soybean oil, etc., and benzylbenzoate, benzyl alcohol etc. as a solubilizer may be jointly used.Injections thus prepared are, in general, filled in appropriateampoules.

The compound represented by the formula (I") or a salt thereof can beused safely with low toxicity. Although the daily dose varies dependingon the condition and weight of the patient, kind of the compound, routeof administration and other factors, for example, in the case ofadministering the compound of the present invention for the therapy ofhypercholesteremia, a daily oral dosage per adult human is about 1 to500 mg, preferably about 10 to 200 mg. Within this range, no toxicity isobserved at all.

The compound of the formula (I") for squalene synthetase inhibition iseffectively administered to a mammal, e.g., human, in a therapeuticallyeffective amount which is generally provided with an oral daily dosageper adult of from about 1 to about 500 mg, preferably about 10 to 200mg. In terms of a non-oral dosage range such as for an injection orsuppository, a therapeutically effective amount is generally in therange of from about 0.1 to about 100 mg/day, preferably about 1 to 20mg/day.

The present invention compounds also demonstrate broad spectrumantifungal activity as determined by broth or agar dilution methods.

In case of administering the compound of the present invention for thetherapy of fungus infections, generally from 2 to 5 mg/kg should beemployed as a unit dosage in an antifungal treatment.

The compound of the formula (I") for fungus treatment is effectivelyadministered to a mammal, e.g., human, in a therapeutically effectiveamount which is generally provided with an oral daily dosage per adultof from about 0.1 to about 100 mg, preferably about 1 to 50 mg. In termsof a non-oral dosage range such as for an injection or suppository, atherapeutically effective amount is generally in the range of from about0.1 to about 100 mg/day, preferably about 1 to 50 mg/day.

Abbreviations for amino acids, and other used in the presentspecification are based on abbreviations specified by the IUPAC-IUBCommission on Biochemical Nomenclature or abbreviations in common use inrelevant fields. Some examples are given below. When an optical isomermay be present in amino acid, it is of the L-configuration, unlessotherwise stated.

Trp or Y: Tryptophan

Ser or S: Serine

Asp or D: Aspartic acid

Glu or E: Glutamic acid

Me: Methyl

Et: Ethyl

Ph: Phenyl

EXAMPLE!

The following examples, reference examples, formulation examples andtest examples are intended to illustrate the present invention infurther detail and should by no means be construed as defining the metesand bounds of the invention.

In the following description, two types of racemic diastereomers areobtained depending of the kinds of compounds, which is due to thepresence of asymmetric carbon atoms at 3- and 5-positions. Isomers inwhich the substituents at 3- and 5-positions are oriented in the samedirection relative to the face of 7-membered ring are named cis-isomers,while those in which the substituents at 3- and 5-positions are orientedin the adverse directions to each other are named transisomers.

Reference Example 1Trans-7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-1-methyl-2-oxo-4,1-benzoxazepine-3-aceticacid ethyl ester

(1) Ethyl 3- N- 2-(2-chlorobenzoyl)-4-chlorphenyl!carbamoyl!acrylate

To a suspension of 5.0 g of 2-amino-5-chloro-2'-chlorobenzophenone and2.5 g of sodium hydrogencarbonate in 100 ml of methylene chloride wasadded dropwise 3.3 g of monoethyl ester of fumaric acid semi-chloride inthe course of 30 minutes. The mixture was stirred for 2 hours at roomtemperature, to which was then added water, followed by shaking. Theorganic layer was separated, which was dried over anhydrous sodiumsulfate, followed by distilling off the solvent under reduced pressureto leave 4.8 g of 3- N-2-(2-chlorobenzoyl)-4-chlorophenyl!carbamoyl!acrylic acid ethyl ester ascrystals, m.p. 113°-114° C.

Elemental Analysis for C₁₉ H₁₅ Cl₂ NO₄ : Calcd.: C 58.18; H 3.85; N 3.57Found: C 58.27; H 3.88; N 3.48

(2) Ethyl ester of 3- N- 2-(2-chlorobenzoyl)-4-chlorophenyl!-N-methylcarbamoyl!acrylic acid

To a suspension of 0.15 g of sodium hydride in 20 ml ofN,N-dimethylformamide was added, while stirring under ice-cooling, 3.0 gof the crystals obtained above. The mixture was stirred for 10 minutesat 0° C., to which was added 2.0 g of methyl iodide, then the mixturewas stirred for 2 hours at room temperature. The reaction mixture waspoured into ice-water, which was subjected to extraction with ethylacetate. The ethyl-acetate layer was washed with water and dried, fromwhich the solvent was distilled off under reduced pressure to leave 2.8g of ethyl ester of 3- N- 2-(2-chlorobenzoyl)-4-chlorophenyl!-N-methylcarbamoyl!acrylic acid as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1725(C═O), 1670(C═O), 1490, 1370, 1300, 1180,1115, 920, 740

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 1.27(3H,t,CH₂ CH₃), 3.18(3H,s,--NCH₃), 4.18(2H,q, CH₂ CH₃), 6.78(2H,d,--CH═CH--), 7.1-7.7(7H,m)

(3) Ethyl ester of 3- N-4-chloro-2-(α-hydroxy-2-chlorobenzyl)phenyl!-N-methylcarbamoyl!acrylicacid

In 50 ml of methanol was dissolved 2.8 g of the oily product obtainedabove, to which was added 0.2 g of sodium borohydride, and the mixturewas stirred for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure, which was subjected to extractionwith ethyl acetate. The organic layer was washed with water, dried andsubjected to distillation under reduced pressure. Crystallization of theresidue afforded 2.4 g of ethyl ester of 3- N-4-chloro-2-(α-hydroxy-2-chlorobenzyl)phenyl!-N-methylcarbamoyl!acrylicacid, m.p. 128°-130° C.

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₄.1/4H₂ O: Calcd.: C 58.19; H,4.76; N 3.39 Found: C 58.38; H, 4.79; N 3.31

(4) Ethyltrans-7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-1-methyl-2-oxo-4,1-benzoxazepine-3-acetate

In 30 ml of ethanol was dissolved 2.2 g of the crystals obtained above,to which was added 1.5 g of potassium carbonate, and the mixture wasstirred for 3 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure. To the concentrate was added water,which was subjected to extraction with ethyl acetate. The organic layerwas washed with water and dried, followed by distilling off the solventunder reduced pressure. The residue was purified by means of a silicagel chromatography (eluent, hexane:ethyl acetate=3:1) to afford 1.85 gof ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-1-methyl-2-oxo-4,1-benzoxazepine-3-aceticacid as crystals, m.p. 147°-148° C.

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₄ : Calcd.: C 58.84; H 4.69; N 3.43Found: C 58.76; H 4.79; N 3.28

Reference Example 2 Ethyltrans-7-chloro-5-(2-chlorophenyl)-1-cyclohexylmethyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetate

(1) N-cyclohexylmethyl-4-chloro-2-α-hydroxy-(2-chlorophenyl)methyl!aniline

In 50 ml of glacial acetic acid was dissolved 5.0 g of 4-chloro-2-α-hydroxy-(2-chlorophenyl)methyl!aniline. To the solution was added 2.5g of cyclohexane carboxaldehdye. To the mixture was added, whilestirring under ice-cooling, 1.06 g of sodium borohydride in the courseof 40 minutes. The reaction mixture was poured into ice-water, which wassubjected to extraction with ethyl acetate. The organic layer was washedwith a dilute aqueous solution of sodium hydroxide, then with water,followed by drying. The solvent was distilled off under reduced pressureto leave 6.2 g of N-cyclohexylmethyl-4-chloro-2-α-hydroxy-(2-chlorophenyl)methyl!aniline as crystals, m.p. 91°-92° C.

Elemental Analysis for C₂₀ H₂₃ Cl₂ NO: Calcd.: C 65.94; H 6.36; N 3.84Found: C 65.79; H 6.32; N 3.71

(2) Ethyl ester of 3- N- 4-chloro-2-(α-hydroxy-2-chlorophenylmethyl)phenyl!-N-cyclohexylmethylcarbamoyl!acrylic acid

In 80 ml of methylene chloride was dissolved 6.0 g the crystals obtainedabove. To the solution was added dropwise, while stirring underice-cooling, 2.8 g of monoethyl ester of fumaric acid chloride (asolution in 20 l of methylene chloride) in the course of 30 minutes. Thereaction mixture was stirred for 20 minutes at room temperature, whichwas washed with water, dried and subjected to concentration underreduced pressure. The concentrate was purified by means of a silica gelchromatography (eluent, hexane:ethyl acetate=3:1) to afford 6.5 g ofethyl ester of 3- N-4-chloro-2-(α-hydroxy-2-chlorophenylmethyl)phenyl!-N-cyclohexylmethylcarbamoyl!acrylicacid as an oily product.

IRν_(max) ^(Heat) cm⁻¹ : 3400(OH), 2940, 1730(C═O), 1660(C═O), 1630,1300, 1180, 1040

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 0.8-2.0(14H, multiplet, CH₂ CH₃-cyclohexane), 2.6-3.5(2H, multiplet, --N CH₂ -cyclohexane), 4.0-4.5(2H,multiplet, CH₂ CH₃), 6.05-7.7(10H, multiplet)

(3) Ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-cyclohexylmethyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

In 100 ml of ethanol was dissolved 6.5 g of the oily product obtainedabove, to which was added 5 g of potassium carbonate, and the mixturewas stirred for 15 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure. The concentrate was subjected toextraction with ethyl acetate. The organic layer was washed with waterand dried, from which was distilled off the solvent under reducedpressure. The residue was purified by means of a silica gelchromatography (eluent, hexane:ethyl acetate=8:1) to afford 5.2 g ofethyl ester of3,5-trans-7-chloro-5-(2-chlorophenyl)-1-cyclohexylmethyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid as a powdery product.

IRν_(max) ^(Neat) cm⁻¹ : 2940, 1740(C═O), 1680(C═O), 1600, 1490, 1380,1270

Elemental Analysis for C₂₆ H₂₉ Cl₂ NO₄ : Calcd.: C 63.68; H 5.96; N 2.86Found: C 63.48; H 5.98; N 2.71

Reference Example 3

By substantially the same procedure as in Reference Example 2, compoundsshown in Table 1 through Table 4 were obtained.

                                      TABLE 1    __________________________________________________________________________     ##STR40##    Compd.               m.p.        Elemental Analysis (Found)    No. R.sub.1       R.sub.2                         (°C.)                              Formula                                     C       H       N    __________________________________________________________________________    1   H             C.sub.2 H.sub.5                         148-150                              C.sub.19 H.sub.17 Cl.sub.2 NO.sub.4                                     57.88   4.35    3.55                                     (57.92) (4.60)  (3.33)         ##STR41##    C.sub.2 H.sub.5                         126-127                              C.sub.26 H.sub.23 Cl.sub.2 NO.sub.4                                     64.47 (64.67)                                             4.79 (4.65)                                                     2.89 (2.91)    3         ##STR42##    C.sub.2 H.sub.5                         oil  C.sub.27 H.sub.25 Cl.sub.2 NO.sub.5                                     IRν.sup.neat .sub.max cm.sup.-1 :                                     2980, 1735(CO), 1680(CO) .sup.1 H-NMR(CDC                                     l.sub.3)δ: 1.26(3H, t, CH.sub.2                                     CH.sub.3), 2.82(1H, dd), 3.13(1H,                                     dd)3.67(3H, s, OCH.sub.3), 4.16(2H, q,                                     CH.sub.2 CH.sub.3), 4.51(1H, dd, C.sub.3                                     -H)    4         ##STR43##    C.sub.2 H.sub.5                         135-136                              C.sub.27 H.sub.25 Cl.sub.2 NO.sub.5                                     63.04 (62.84)                                             4.90 (5.02)                                                     2.72 (2.70)    __________________________________________________________________________

                                      TABLE 2    __________________________________________________________________________    Compd.             m.p.         Elemental Analysis (Found)    No. R.sub.1     R.sub.2                       (°C.)                            Formula C       H        N    __________________________________________________________________________         ##STR44##  C.sub.2 H.sub.5                       oil  C.sub.27 H.sub.25 Cl.sub.2 NO.sub.4                                    IRν.sup.neat .sub.max cm.sup.-1 :                                    3000, 1740(CO), 1680(CO), 1490, 1170                                    .sup. H-NMR(CDCl.sub.3)δ: 1.26(3H,                                    t, CH.sub.2 CH.sub.3), 3.8(1H, dd,                                    C.sub.3 -H), 4.15(2H, q, CH.sub.2                                    CH.sub.3), 6.04(1H, s, C.sub.5 -H)    6         ##STR45##  C.sub.2 H.sub.5                       142-143                            C.sub.30 H.sub.25 Cl.sub.2 NO.sub.4                                    67.42 (67.38)                                            4.71 (4.89)                                                     2.62 (2.45)    7   CH(CH.sub.3).sub.2                    C.sub.2 H.sub.5                       oil  C.sub.22 H.sub.23 Cl.sub.2 NO.sub.4                                    IRν.sup.neat .sub.max cm.sup.-1 :                                    2980, 1740(CO), 1670(CO)                                    .sup.1 H-NMR(CDCl.sub.3)δ:                                    1.1-1.6(9H, m, CH.sub.2 CH.sub.3,                                    CH(CH.sub.3).sub.2),                                    2.77(1H, dd), 3.07(1H, dd), 4.13(2H, q),                                    4.33(1H, t, C.sub.3 -H),                                    6.01(1H, s, C.sub.5 -H)    8         ##STR46##  C.sub.2 H.sub.5                       186-187                            C.sub.28 H.sub.24 Cl.sub.2 N.sub.2 O.sub.4                                    64.25 (64.02)                                            4.62 (4.69)                                                     5.35 (5.39)    __________________________________________________________________________

                                      TABLE 3    __________________________________________________________________________    Compd.           m.p.        Elemental Analysis (Found)    No. R.sub.1   R.sub.2                     (°C.)                          Formula                                 C       H        N    __________________________________________________________________________     9  C.sub.2 H.sub.5                  C.sub.2 H.sub.5                     119-120                          C.sub.21 H.sub.21 Cl.sub.2 NO.sub.4                                 59.73   5.01     3.32                                 (59.60) (4.95)   (3.35)    10         ##STR47##                  C.sub.2 H.sub.5                     oil  C.sub.24 H.sub.25 Cl.sub.2 NO.sub.4                                 .sup.1 H-NMR(CDCl.sub.3)δ: 1.25(3H, t,                                 CH.sub.2 CH.sub.3), 1.5-2.4(8H, m), 2.78,                                 3.05(2H, both, dd), 4.15(2H, m), 4.31(1H,                                 dd, C.sub.3 -H), 4.69(1H, t), 6.01(1H, s,                                 C.sub.5 -H), 6.50(1H, d, C.sub.6 -H),                                 7.2-7.6(6H, m)    11         ##STR48##                  C.sub.2 H.sub.5                     oil  C.sub.24 H.sub.21 Cl.sub.2 NO.sub.5                                 .sup.1 H-NMR(CDCl.sub.3)δ: 1.24(3H, t,                                 CH.sub.3), 2.82, 3.10(2H, both both, dd),                                 4.14(2H, q, CH.sub.2 CH.sub.3), 4.46(1H, dd,                                 C.sub.3 -H), 4.85, 5.5(2H, both, d),                                 5.93(1H, s, C.sub.5 -H), 6.2-6.5(3H, m),                                 7.2-7.7(7H, m)    __________________________________________________________________________

                                      TABLE 4    __________________________________________________________________________    Compd.            m.p.          Elemental Analysis (Found)    No. R.sub.1    R.sub.2                      (°C.)                           Formula  C   H    N    __________________________________________________________________________    12  --CH.sub.3 --CH═C(CH.sub.3).sub.3                   C.sub.2 H.sub.6                      oil  C.sub.24 H.sub.25 Cl.sub.3 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ:                                    1.25(3H,                                    t, CH.sub.3), 1.65(6H, d, CH.sub.3                                    × 2),                      2.8.3.8(2H, both dd), 4.05-4.3(3H, m), 4.42(1H,                      dd)4.9-5.4                      (2H, m), 6.0(1H, s, C.sub.6 -H), 6.49(1H, d),                      7.2-7.7(6H, m)    13  --CH.sub.3 --C(CH.sub.3)═CH.sub.2                   C.sub.2 H.sub.6                      oil  C.sub.23 H.sub.33 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ:                                    1.25(3H,                                    t, CH.sub.3), 1.82(3H, s, CH.sub.3),                      2.80, 3.13(2H, both dd), 4.13(2H, q, CH.sub.2 CH.sub.3),                       4.40, 4.67(2H,                      both d), 4.53(1H, dd, C.sub.3 -H), 4.97(2H, m),                      6.05(1H, s), 6.5(1H, d),                      7.2-7.8(6H, m)    14  --CH.sub.2 --CH═CH.sub.2                   C.sub.2 H.sub.6                      126-127                           C.sub.22 H.sub.21Cl.sub.2 NO.sub.4                                    60.84                                        4.87 3.23                                    (60.91)                                        (4.90)                                             (3.06)    15  --CH.sub.2 --C.tbd.CH                   C.sub.2 H.sub.6                      oil  C.sub.22 H.sub.19 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ:                                    1.25(3H,                                    t, CH.sub.3), 2.82, 3.08 (2H, both dd),                      4.14(2H, q, CH.sub.2 CH.sub.3), 4.47(1H, dd, C.sub.3                      -H), 4.55, 4.95(2H,                      both dd), 6.10(1H, s, C.sub.5 -H), 6.53(1H, d),                      7.3-7.75(1H, m)    16  --CH.sub.3 CH.sub.3 CH.sub.3                   C.sub.2 H.sub.5                      oil  C.sub.22 H.sub.23 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.97                                    (3H, t, CH.sub.3), 1.25(3H, t),                      1.5-1.9(2H, m), 2.78, 3.07(2H, both dd), 3.53(1H, m),                      4.13(2H, dq),                      4.4(2H, m), 6.03(1H, s), 6.50(1H, d), 7.2-7.8(6H,    __________________________________________________________________________                      m)

Example 1

By substantially the same procedure as in Reference Example 2, compoundsshown in Table 5 and Table 6 were obtained

                                      TABLE 5    __________________________________________________________________________    Compd.            m.p.          Elemental Analysis (Found)    No. R.sub.1    R.sub.2                      (°C.)                           Formula  C   H    N    __________________________________________________________________________    1   --(CH.sub.2).sub.2 CH.sub.3                   C.sub.2 H.sub.6                      80-81                           C.sub.26 H.sub.31 Cl.sub.2 NO.sub.4                                    63.42                                        6.35 2.84                                    (63.58)                                        (6.58)                                             (2.19)    2   --CH.sub.2 CH(CH.sub.3).sub.2                   C.sub.2 H.sub.5                      oil  C.sub.13 H.sub.25 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.92,                                    1.03(6H, both d, CH.sub.3), 1.25 (3H,                      t, CH.sub.3), 1.98(1H, m), 2.8, 3.06(2H, both dd),                      3.45(1H, dd),                      4.13(2H, q), 4.2-4.5(2H, m), 6.14(1H, s, C.sub.5 -H),                      6.51(1H, d)                      7.2-7.8(6H, m)    3   --CH.sub.2 CH(C.sub.2 H.sub.5).sub.2                   C.sub.2 H.sub.5                      oil  C.sub.25 H.sub.29 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.85,                                    0.89(6H, both t, CH.sub.3), 1.25(3H,                      t, CH.sub.3), 1.2-1.7(4H, m), 2.8, 3.05(2H, both dd),                      4.14(2H, q,                      CH.sub.2 CH.sub.3), 3.45(1H, dd), 4.45(2H, m), 6.11(1H,                      s, C.sub.6 -H),                      6.51(1H, d), 7.2-7.8(6H, m)    4   --CH.sub.2 C(CH.sub.3)hd 3                   C.sub.2 H.sub.5                      101-102                           C.sub.24 H.sub.21 Cl.sub.2 NO.sub.4                                    62.01                                        5.86 3.02                                    (62.36)                                        (5.87                                             (2.99)    5   --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                   C.sub.2 H.sub.5                      oil  C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.91,                                    0.92(6H, both t, CH.sub.3), 1.25(3H,                      t, CH.sub.3), 1.4-1.8(3H, m), 2.79, 3.06(2H, both dd),                      3.55(1H,                      m), 4.05-4.6(4H, m), 6.01(1H, s, C.sub.5 -H, 6.51(1H,                      d),                      7.2-7.8(6H, m)    __________________________________________________________________________

                                      TABLE 6    __________________________________________________________________________    Compd.            m.p.          Elemental Analysis (Found)    No. R.sub.1    R.sub.2                      (°C.)                           Formula  C   H    N    __________________________________________________________________________    6   --CH(C.sub.2 H.sub.5).sub.2                   C.sub.2 H.sub.5                      oil  C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.98,                                    1.04(6H, both t, CH.sub.3), 1.24(3H,                      t), 1.6-2.1(4H, m), 2.76, 3.1(2H, both dd), 4.13, (2H,                      q,                      OCH.sub.2 CH.sub.3), 4.2-4.4(2H, m), 6.09(1H, s,                      C.sub.5 -H), 6.51(1H, d)                      7.2-7.8(6H, m)    7   --(CH.sub.2).sub.3 CH.sub.3                   C.sub.2 H.sub.5                      oil  C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.91(3H,                                    t),                                    1.25(3H, t), 1.3-1.8(4H, m),                      2.78, 3.06(2H, both dd), 3.45-3.63(1H, m), 4.13(2H,                      dq),                      4.35-4.55(2H, m), 6.03(1H, s), 6.51(1H, d), 7.2-7.75                      (6H, m)    __________________________________________________________________________

In Table 7 through Table 12, physicochemical. properties ofintermediates obtained in Reference Example 3 and Example 1 are shown.

                                      TABLE 7    __________________________________________________________________________     ##STR49##                m.p.        Elemental Analysis (Found)    R           (°C.)                     Formula                            C      H       N    __________________________________________________________________________     ##STR50##  oil  C.sub.21 H.sub.19 Cl.sub.2 NO.sub.2                            .sup.1 H-NMR(CDCl.sub.3)δ: 3.77(3H, s,                            OCH.sub.3), 4.29(2H, s), 6.08(1H, s),                            6.55-7.5(11H, m)     ##STR51##  119-120                     C.sub.21 H.sub.19 Cl.sub.2 NO                            67.75 (67.83)                                   5.14 (5.12)                                           3.76 (3.71)     ##STR52##  oil  C.sub.24 H.sub.19 Cl.sub.2 NO                            .sup.1 H-NMR(CDCl.sub.3)δ: 4.73(2H, s),                            6.09(1H, s), 6.6-8.0(14H, m)    CH(CH.sub.3).sub.2                oil  C.sub.16 H.sub.17 Cl.sub.2 NO                            NMR(CDCl.sub.3)δ: 1.12(3H, d), 1.18(3H, d),                            3.6(1H,                            m), 6.07(1H, m), 6.5-7.5(7H, m)     ##STR53##  oil  C.sub.22 H.sub.18 Cl.sub.2 N.sub.2 O                            .sup.1 H-NMR(CDCl.sub.3)δ: 4.45(2H, s,                            CH.sub.2 -indol), 6.05(1H, s), 6.5-8.2(12H,    __________________________________________________________________________                            m)

                                      TABLE 8    __________________________________________________________________________              m.p.        Elemental Analysis (Found)    R         (°C.)                   Formula                          C      H      N    __________________________________________________________________________    (CH.sub.2).sub.3 CH.sub.3              oil  C.sub.20 H.sub.25 Cl.sub.2 NO                          .sup.1 H-NMR(CDCl.sub.3)δ: 0.87(3H, t,                          CH.sub.3), 1.0-1.7                          (10H, m), 2.8-3.1(2H, m), 6.1-7.7(8H, m)    CH.sub.2 CH(CH.sub.3).sub.2              87-88                   C.sub.17 H.sub.18 Cl.sub.2 NO                          62.97  5.91   4.32                          (62.97)                                 (6.05) (4.44)     ##STR54##              oil  C.sub.18 H.sub.19 Cl.sub.2 NO                          .sup.1 H-NMR(CDCl.sub.3)δ: 1.2-2.2(8H, m),                          3.75(1H, m), 6.05(1H, s), 6.5-7.5(7H, m)     ##STR55##              oil  C.sub.18 H.sub.16 Cl.sub.2 NO.sub.2                          .sup.1 H-NMR(CDCl.sub.3)δ: 3.7(2H, m),                          5.9-6.2(3H, m), 6.8-7.5(8H, m)    CH.sub.2 CH(C.sub.2 H.sub.5).sub.2              oil  C.sub.19 H.sub.23 Cl.sub.2 NO                          .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.6(10H, m),                          2.97(2H,                          d), 6.11(1H, s), 6.6(1H, d), 6.9-7.5(6H, m)    CH.sub.2 C(CH.sub.3).sub.3              110-111                   C.sub.18 H.sub.21 Cl.sub.2 NO                          63.91  6.26   4.14                          (64.12)                                 (6.30) (4.31)    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2              oil  C.sub.18 H.sub.21 Cl.sub.2 NO                          .sup.1 H-NMR(CDCl.sub.3)δ: 0.90, 0.93(6H,                          both, d, CH.sub.3),                          1.4-1.8(3H, m), 3.09(2H, t), 6.12(1H, s),                          6.60(1H, d), 6.90(1H, d), 7.1-7.5(5H,    __________________________________________________________________________                          m)

                                      TABLE 9    __________________________________________________________________________              p.m.       Elemental Analysis (Found)    R         (°C.)                  Formula                         C      H       N    __________________________________________________________________________    --CH.sub.2 CH═C(CH.sub.3).sub.2              oil C.sub.18 H.sub.19 Cl.sub.2 NO                         .sup.1 H-NMR(CDCl.sub.3)δ: 1.66, 1.73 (6H,                         both s, CH.sub.3),                         3.66(2H, d), 6.01(1H, s), 6.59(1H, d), 8.22(1H, d),                         7.1-7.5(6H, m)    --CH.sub.2 C(CH.sub.3)═CH.sub.3              oil C.sub.17 H.sub.17 Cl.sub.2 NO                         .sup.1 H-NMR(CDCl.sub.3)δ: 1.72(3H, s,                         CH.sub.3),                         3.68(2H, s), 4.85(2h, m), 6.15(1H, s),                         6.55(1H, d), 6.86(1H, d), 7.05-7.5(5H, m)    --CH(C.sub.2 H.sub.6).sub.2              oil C.sub.18 H.sub.21 Cl.sub.2 NO                         .sup.1 H-NMR(CDCl.sub.3)δ: 0.75(3H, t,                         CH.sub.3),                         0.88(3H, t, CH.sub.3), 1.1-1.7(4H, m), 3.2(1H, m),                         6.1(1H, s), 6.5-7.5(7H, m)    --CH.sub.2 --CH═CH.sub.2              oil C.sub.18 H.sub.15 Cl.sub.2 NO                         .sup.1 H-NMR(CDCl.sub.3)δ: 3.8(2H, m),                         5.1-6.0(3H, m)                         6.16(1H, s), 6.55-7.5(7H, m), 6.82(1H, d)    --CH.sub.2 C.tbd.CH              oil C.sub.18 H.sub.13 Cl.sub.2 NO                         .sup.1 H-NMR(CDCl.sub.3)δ: 3.95(2H, d),                         6.14(1H, s),                         6.73(1H, d), 6.8(1H, d), 7.1-7.6(6H, m)    --CH.sub.2 CH.sub.2 Ch.sub.3              oil C.sub.16 H.sub.17 Cl.sub.2 NO                         .sup.1 H-NMR(CDCl.sub.3)δ: 0.95(3H, t),                         1.65(2H, m),                         3.06(2H, t), 6.12(1H, s), 6.55-7.5(7H, m)    --(CH.sub.2).sub.3 CH.sub.3              oil C.sub.17 H.sub.19 Cl.sub.2 NO                         .sup.1 Hl-NMR(CDCl.sub.3)δ: 0.92(3H, t),                         1.2-1.7(4H, m),                         3.07(2H, t), 6.10(1H, s), 6.59(1H, d), 6.87(1H, d),                         7.1-7.5(5H, m)    __________________________________________________________________________

                                      TABLE 10    __________________________________________________________________________     ##STR56##                      m.p.      Elemental Analysis (Found)    R.sub.1       R.sub.2                      (°C.)                         Formula                                C       H        N    __________________________________________________________________________     ##STR57##    C.sub.2 H.sub.5                      oil                         C.sub.27 H.sub.25 Cl.sub.2 NO.sub.4                                .sup.1 H-NMR(CDCl.sub.3)δ: 1.2(3H, t,                                CH.sub.2 CH.sub.3), 3.5(3H, s, OCH.sub.3),                                4.06(2H, q, CH.sub.2 CH.sub.3), 4.68(1H, d),                                5.55(1H, d), 6.0-7.7(14H, m)     ##STR58##    C.sub.2 H.sub.5                      oil                         C.sub.27 H.sub.25 Cl.sub.2 NO.sub.5                                .sup.1 H-NMR(CDCl.sub.3)δ: 1.2(3H, t,                                CH.sub.2 CH.sub.3), 3.76(3H, s, OCH.sub.3),                                4.05(2H, q, CH.sub.2 CH.sub.3), 4.24(1H, d),                                5.65(1H, d) 6.1-7.6(14H, m)     ##STR59##    C.sub.2 H.sub.5                      oil                         C.sub.27 H.sub.25 Cl.sub.2 NO.sub.4                                .sup.1 H-NMR(CDCl.sub.3)δ: 1.1-1.4(3H,                                m), 2.7-4.7(6H, m), 6.0-7.7(15H,    __________________________________________________________________________                                m)

                                      TABLE 11    __________________________________________________________________________                    p.m.         Elemental Analysis (Found)    R.sub.1     R.sub.2                    (°C.)                         Formula C     H     N    __________________________________________________________________________     ##STR60##  C.sub.2 H.sub.5                    oil  C.sub.30 H.sub.25 Cl.sub.2 NO.sub.4                                 .sup.1 H-NMR(CDCl.sub.3)δ: 1.13(3H, t,                                 CH.sub.2 CH.sub.3) 4.1(2H, q, CH.sub.2                                 CH.sub.3), 5.02(1H, d), 5.9-8.2(18H, m)     ##STR61##  C.sub.2 H.sub.5                    oil  C.sub.28 H.sub.24 Cl.sub.2 N.sub.2 O.sub.4                                 .sup.1 H-NMR(CDCl.sub.3)δ: 1.1-1.4(3H,                                 m), 3.9-4.3(2H, m), 4.6-5.8(2H,                                 m), 6.0-8.4(15H, m)    C.sub.2 H.sub.5                C.sub.2 H.sub.5                    oil  C.sub.21 H.sub.21 Cl.sub.2 NO.sub.4                                 .sup.1 H-NMR(CDCl.sub.3)δ: 0.9-1.5(6H,                                 m),                                 3.5-4.5(4H, m), 6.0-7.9(10H, m)    (CH.sub.2).sub.6 CH.sub.3                C.sub.2 H.sub.5                    oil  C.sub.28 H.sub.31 Cl.sub.2 NO.sub.4                                 .sup.1 H-NMR(CDCl.sub.3)δ: 0.85(3H, t,                                 CH.sub.3),                                 0.95-1.7(13H, m), 2.7-4.5(4H, m)                                 6.0-7.7(10H, m)    CH.sub.2 CH(CH.sub.3).sub.2                C.sub.2 H.sub.5                    136-138                         C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                                 61.34 5.59  3.11                                 (61.26)                                       (5.71)                                             (3.06)     ##STR62##  C.sub.2 H.sub.5                    192-194                         C.sub.24 H.sub.25 Cl.sub.2 NO.sub.4                                 62.34 (62.05)                                       5.45 (5.50)                                             3.03 (3.07)     ##STR63##  C.sub.2 H.sub.5                    oil  C.sub.24 H.sub.21 Cl.sub.2 NO.sub.5                                 .sup.1 H-NMR(CDCl.sub.3)δ: 1.27(3H, m,                                 CH.sub.3), 3.6(1H, m), 4.15(2H, m,                                 CH.sub.2), 5.35(1H, m), 5.9-8.0(13H,    __________________________________________________________________________                                 m)

                                      TABLE 12    __________________________________________________________________________                   p.m         Elemental Analysis (Found)    R.sub.1    R.sub.2                   (°C.)                        Formula                               C       H      N    __________________________________________________________________________    --CH.sub.2 CH(C.sub.2 H.sub.5).sub.2               --C.sub.2 H.sub.5                   oil  C.sub.25 H.sub.23 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.6-1.7(14H,                               m),                               2.7-4.6(4H, m), 5.9-7.7(10H, m)    --CH.sub.2 C(CH.sub.2).sub.3               --C.sub.2 H.sub.5                   oil  C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.4(12H,                               m),                               2.8-4.6(4H, m), 6.1-7.7(10H, m)    --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2               --C.sub.2 H.sub.5                   oil  C.sub.24 H.sub.21 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.6-1.7(12H,                               m),                               2.6-4.6(4H, m), 5.9-7.7(10H, m)    --CH.sub.2 --CH═C(CH.sub.3).sub.2               --C.sub.2 H.sub.5                   oil  C.sub.24 H.sub.25 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 1.1-1.9(9H,                               m),                               3.9-4.9(4H, m), 6.0-7.7(11H, m)    --CH.sub.2 --C(CH.sub.3)═CH.sub.3               --C.sub.2 H.sub.5                   oil  C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 1.25(3H, m),                               1.77 (3H, m),                               3.0-5.2(6H, m), 5.9-7.9(10H, m)    --CH(C.sub.2 H.sub.5).sub.3               --C.sub.2 H.sub.5                   oil  C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-2.1(13H,                               m),                               4.0-4.4(3H, m), 6.0-7.5(10H, m)    --CH.sub.2 --CH═CH.sub.2               --C.sub.2 H.sub.5                   oil  C.sub.22 H.sub.21 Cl.sub.3 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 1.15-1.4(3H,                               m,                               CH.sub.3), 3.1-6.0(7H, m), 6.1-7.7(10H, m)    --CH.sub.2 --C.tbd.CH               --C.sub.2 H.sub.5                   132-133                        C.sub.22 H.sub.19 Cl.sub.2 NO.sub.4                               61.12   4.43   3.24                               (61.02) (4.67) (3.13)    --CH.sub.2 CH.sub.3 CH.sub.3               --C.sub.2 H.sub.5                   oil  C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.77,                               0.86(3H, hoth d), 1.22, 1.24                               (3H, both t), 1.4-1.9(2H, m), 2.6-4.5(4H, m),                               6.0-7.6                               (10H, m)    --(CH.sub.3).sub.3 CH.sub.3               --C.sub.2 H.sub.5                   oil  .sub.C23 H.sub.25 Cl.sub.2 NO.sub.4                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.9(10H,                               m), 2.6-4.5(4H, m),                               5.9-7.7(10H, m)    __________________________________________________________________________

Reference Example 4Trans-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

In a mixture of 10 ml of methanol and 4 ml of water was suspended 0.5 gof ethyl ester of3,5-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid. To the suspension was added 0.8 g of potassium carbonate, and themixture was stirred for 3 hours at 60° C. The reaction mixture wasconcentrated under reduced pressure, to which was added water, followedby extraction with ether. The aqueous layer was acidified with dilutehydrochloric acid, followed by extraction with ethyl acetate. Theorganic layer was washed with water and dried, followed by concentrationunder reduced pressure. The concentrate was purified by means of asilica gel chromatography to afford 0.21 g of3,5-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid as crystals, m.p. 211°-213° C.

Elemental Analysis for C₁₈ H₁₅ Cl₂ NO₄ : Calcd.: C 56.86; H 3.98; N 3.68Found : C 56.86; H 4.24; N 3.53

Reference Example 5

By substantially the same procedure as in Reference Example 4, compoundsshown in Table 13 through Table 15 were obtained.

                                      TABLE 13    __________________________________________________________________________     ##STR64##    Compd.            m.p.        Elemental Analysis (Found)    No. R             (°C.)                           Formula                                  C   H   N    __________________________________________________________________________         ##STR65##    175-178                           C.sub.24 H.sub.19 Cl.sub.2 NO.sub.4                                  63.17 (63.18)                                      4.20 (4.24)                                          3.07 (3.23)    2         ##STR66##    213-214                           C.sub.25 H.sub.21 Cl.sub.2 NO.sub.5                                  61.74 (61.55)                                      4.35 (4.55)                                          2.88 (2.79)    3         ##STR67##    165-167                           C.sub.25 H.sub.21 Cl.sub.2 NO.sub.5                                  61.74 (61.49)                                      4.35 (4.47)                                          2.88 (2.84)    __________________________________________________________________________

                                      TABLE 14    __________________________________________________________________________    Compd.          p.m.        Elemental Analysis (Found)    No. R           (°C.)                         Formula                                C   H   N    __________________________________________________________________________         ##STR68##  212-214                         C.sub.25 H.sub.21 Cl.sub.2 NO.sub.4                                63.84 (63.94)                                    4.50 (4.71)                                        2.98 (3.17)    5         ##STR69##  243-244                         C.sub.28 H.sub.21 Cl.sub.2 NO.sub.4                                66.41 (66.27)                                    4.18 (4.05)                                        2.77 (2.65)    6         ##STR70##  241-242                         C.sub.24 H.sub.25 Cl.sub.2 NO.sub.4                                62.34 (62.27)                                    5.45 (5.45)                                        3.03 (3.02)    7   CH(CH.sub.3).sub.2                    208-209                         C.sub.20 H.sub.19 Cl.sub.2 NO.sub.4                                58.84                                    4.69                                        3.43                                (58.78)                                    (4.83)                                        (3.38)    __________________________________________________________________________

                                      TABLE 15    __________________________________________________________________________    Compd.         p.m.         Elemental Analysis (Found)    No. R          (°C.)                        Formula C   H   N    __________________________________________________________________________     8  C.sub.2 H.sub.5                   215-216                        C.sub.19 H.sub.17 Cl.sub.2 NO.sub.4                                57.88                                    4.35                                        3.55                                (57.67)                                    (4.27)                                        (3.54)     9         ##STR71## 224-225                        C.sub.22 H.sub.21 Cl.sub.2 NO.sub.4                                60.84 (60.64)                                    4.87 (4.94)                                        3.22 (3.32)    10         ##STR72## 190-191                        C.sub.22 H.sub.17 Cl.sub.2 NO.sub.5                                59.21 (58.99)                                    3.84 (3.78)                                        3.14 (3.10)    11  CH.sub.2CHC(CH.sub.3).sub.2                   154-155                        C.sub.22 H.sub.21 Cl.sub.2 NO.sub.4                                60.84                                    4.87                                        3.22                                (60.54)                                    (5.15)                                        (3.31)    12  CH.sub.2C(CH.sub.3)CH.sub.2                   241-242                        C.sub.21 H.sub.19 Cl.sub.2 NO.sub.4                                60.01                                    4.56                                        3.33                                (59.76)                                    (4.73)                                        (3.22)    13  CH.sub.2CHCH.sub.2                   199-200                        C.sub.20 H.sub.17 Cl.sub.2 NO.sub.4                                59.13                                    4.22                                        3.45                                (58.88)                                    (4.30)                                        (3.58)    14  CH.sub.2CCH                   184-185                        C.sub.20 H.sub.15 Cl.sub.2 NO.sub.4                                59.42                                    3.74                                        3.46                                (59.18)                                    (3.75)                                        (3.23)    15  CH.sub.2 CH.sub.2 CH.sub.3                   189-190                        C.sub.2 OH.sub.19 Cl.sub.2 NO.sub.4                                58.84                                    4.69                                        3.43                                (58.78                                    4.95                                        3.60)    __________________________________________________________________________

Example 2

By substantially the same procedure as in Reference Example 4, compoundsshown in Table 16, were obtained.

                                      TABLE 16    __________________________________________________________________________     ##STR73##                   p.m.        Elemental Analysis (Found)    Compd. No.          R        (°C.)                        Formula                               C   H   N    __________________________________________________________________________    1     (CH.sub.2).sub.6 CH.sub.3                   188-189                        C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                               62.07                                   5.86                                       3.02                               (62.21)                                   (5.83)                                       (3.00)    2     CH.sub.2 CH(CH.sub.3).sub.2                   220-221                        C.sub.21 H.sub.21 Cl.sub.2 NO.sub.4                               59.73                                   5.01                                       3.32                               (59.98)                                   (5.24)                                       (3.14)    3     CH.sub.2 CH(C.sub.2 H.sub.5).sub.2                   188-189                        C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                               61.34                                   5.60                                       3.11                               (61.39)                                   (5.74)                                       (2.99)    4     CH.sub.2C(CH.sub.3).sub.3                   247-248                        C.sub.22 H.sub.23 Cl.sub.2 NO.sub.4                               60.56                                   5.31                                       3.21                               (60.55)                                   (5.47)                                       (3.11)    5     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                   166-167                        C.sub.22 H.sub.23 Cl.sub.2 NO.sub.4                               60.56                                   5.31                                       3.21                               (60.40)                                   (5.49)                                       (3.22)    6     CH(C.sub.2 H.sub.5).sub.2                   220-221                        C.sub.22 H.sub.23 Cl.sub.2 NO.sub.4                               60.56                                   5.31                                       3.21                               (60.45)                                   (5.29)                                       (3.20)    7     (CH.sub.2).sub.3 CH.sub.3                   195-196                        C.sub.21 H.sub.21 Cl.sub.2 NO.sub.4                               59.73                                   5.01                                       3.32                               (59.68                                   4.97                                       3.54)    __________________________________________________________________________

Reference Example 6Trans-1-benzyl-7-chloro-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

0.3 g of the ethyl ester oftrans-1-benzyl-7-chloro-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid disclosed in JPA S57(1982)-35576 was subjected to hydrolysis in themanner to be described in the following Reference Example 4 to afford0.12 g oftrans-1-benzyl-7-chloro-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as a white powdery product.

Example 3 Ethyl ester oftrans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (1) 2-Isobutylamino-α-(o-tolyl)benzyl alcohol

Using 2-amino-α-(o-tolyl)benzyl alcohol (2.5 g) and isobutyl aldehyde(1.17 ml), reaction is conducted in substantially the same manner as inReference Example 2 (1) to give 2-isobutylamino-α-(o-tolyl)benzylalcohol (3.1 g) as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 3400(OH); 1720, 1655, 1630(C═O,C═C)

¹ H-NMR(CDCl₃) δ: 0.7-1.1(6H,m), 1.21(3H,t,J=7.0 Hz), 1.5-2.0(1H,m),2.29(3H,s), 2.0-2.3 and 2.9-3.1(1H, each m), 3.9-4.5(3H,m),5.9-6.4(2H,m), 6.6-6.9(1H,m), 6.95-7.9(8H,m)

(2) Ethyl ester of 3- N-2-(α-hydroxy-2-methylbenzyl)phenyl-N-isobutyl!carbamoyl!acrylic acid

In substantially the same manner as in Reference Example 2 (2),2-isobutylamino-α-(o-tolyl)benzyl alcohol (1.3 g) obtained in (1) abovewas allowed to react with fumaric acid chloride monoethyl ester to giveethyl ester of 3- N-2-(α-hydroxy-2-methylbenzyl)phenyl-N-isobutyl!carbamoyl!acrylic acid(3.1 g) as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 3400(OH); 1720, 1655, 1630(C═C, C═O)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 0.7-1.1(6H,m), 1.21(3H,t,J=7.0 Hz),1.5-2.0(1H,m), 2.29(3H,s), 2.0-2.3 and 2.9-3.1(1H, each m),3.9-4.5(3H,m), 5.9-6.4(2H,m), 6.6-6.9(1H,m), 6.95-7.9(8H,m)

(3) Ethyl ester oftrans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In the same manner as in Reference Example 2 (3), ethyl ester of 3- N-2-(α-hydroxy-2-methylbenzyl) phenyl-N-isobutyl!carbamoyl!acrylic acid(1.8 g) was subjected to reaction. The reaction product was crystallizedfrom water-ethanol to give ethyl ester oftrans-1-isobutyl-2-oxo-5-(o-toluyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (2,41 g) as prisms, 88° C.-90° C.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1670(C═O)

Elemental Analysis for C₂₄ H₂₉ NO₄ : Calcd.: C 72.89; H 7.39; N 3.54Found: C 73.18; H 7.25; N 3.54

Example 4

By substantially the same synthetic procedure as in Example 3, compoundslisted in Table 17 and Table 18 were obtained.

                                      TABLE 17    __________________________________________________________________________     ##STR74##    Compd.    p.m.       Elemental Analysis (Found)    No. X   Y (°C.)                  Formula                         C        H       N    __________________________________________________________________________    1   H   Cl              99-100                  C.sub.23 H.sub.28 ClNO.sub.4                         66.42    6.30    3.37                         (66.20)  (6.57)  (3.42)    2   (7)-CH.sub.3            Cl              oil C.sub.24 H.sub.28 ClNO.sub.4                         .sup.1 H-NMR(CDCl.sub.3)δ: 0.92, 1.03(6H,                         both, d, CH.sub.3), 1.25(3H,                         t, CH.sub.2 CH.sub.3), 2.19(3H, s, CH.sub.3), 2.8,                         3.03(2H, both, dd), 3.45                         (1H, dd), 4.13(2H, q, CH.sub.2 CH.sub.3),                         4.2-4.5(2H, m), 6.16(1H,                         s, C.sub.6 -H), 6.31(1H, s, C.sub.6 -H), 7.1-7.8(6H,                         m)    3   (7)-Cl            F oil C.sub.23 H.sub.25 ClFNO.sub.4                         .sup.1 H-NMR(CDCl.sub.3)δ: 0.89, 0.97(6H,                         both, d, CH.sub.3), 1.26(3H,                         t, CH.sub.2 CH.sub.3), 2.04(1H, m), 2.78, 3.07(2H,                         both, dd), 3.4(1H,                         dd), 4.13(2H, q), 4.2-4.5(2H, m), 6.13(1H, s,                         C.sub.6 -H),                         6.63(1H, d), 7.0-7.7(6H, m)    __________________________________________________________________________

                                      TABLE 18    __________________________________________________________________________    Compd.            m.p.          Elemental Analysis (Found)    No. X         Y   (°C.)                           Formula  C    H    N    __________________________________________________________________________         ##STR75##                  Cl  oil  C.sub.26 H.sub.30 ClNO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.93,                                    1.04(6H, both d), 1.9-2.2                      3H, m), 2.7-3.15(6H, m), 3.48(1H, dd), 4.0-4.5(4H, m),                      6.16(1H, s, C.sub.6 -H), 6.35(1H, s, C.sub.6 -H),                      1.1-7.8(5H, m)    5   H         F   oil  C.sub.23 H.sub.18 FNO.sub.4                                    .sup.1 H-NMR(CDCl.sub.3)δ: 0.89,                                    (3H, d), 0.98(3H, d), 1.24(3H,                      t), 1.9-2.2(1H, m), 2.78(1H, dd), 3.06(1H, dd), 3.46                      (1H, dd), 4.13(2H, q), 4.25-4.5(2H, m), 6.18(1H, s)                      6.67(1H, d), 6.9-7.75(7H, m)    6   H         OCH.sub.3                      132-133                           C.sub.24 H.sub.20 NO.sub.5                                    70.05                                         7.10 3.40                                    (70.20)                                         (7.13)                                              (3.56)    __________________________________________________________________________

In Table 19 through Table 22, physicochemical properties ofintermediates are shown.

                                      TABLE 19    __________________________________________________________________________     ##STR76##           m.p.       Elemental Analysis (Found)    X    Y (°C.)              Formula C   H   N    __________________________________________________________________________    H    Cl           oil              C.sub.17 H.sub.20 ClNO                      .sup.1 H-NMR(CDCl.sub.3)δ: 0.8-1.1(6H, m),                      1.9(1H, m), 2.95(2H, d), 5.29(1H,                      s), 6.17(1H, s), 6.5-7.6(7H, m)    (4)-CH.sub.3         Cl           oil              C.sub.18 H.sub.22 ClNO                      .sup.1 H-NMR(CDCl.sub.3)δ: 0.8-1.1(6H, m),                      1.85(1H, m), 2.18(3H, s, CH.sub.3), 2.91                      (2H, d), 6.16(1H, s), 6.55-7.6(7H, m)    (4)-Cl         F oil              C.sub.17 H.sub.19 ClFNO                      .sup.1 H-NMR(CDCl.sub.3)δ: 0.8-1.1(6H, m,                      CH.sub.3), 1.85(1H, m), 2.89(2H, d, NHCH.sub.2),                      6.05(1H, s), 6.57(1H, d), 6.9-7.5                      (6H, m)    __________________________________________________________________________

                                      TABLE 20    __________________________________________________________________________                  m.p.        Elemental Analysis (Found)    X         Y   (°C.)                      Formula C     H    N    __________________________________________________________________________     ##STR77##              Cl  oil C.sub.20 H.sub.24 ClNO                              .sup.1 H-HMR(CDCl.sub.3)δ: 0.8-1.1(6H,                              m), 1.7-2.1(3H, m), 2.6-3.0(6H, m), 6.17(1H,                              s), 6.62(1H, s), 6.68(1H, s), 1.2-7.6(4H, m)    H         F   oil C.sub.17 H.sub.20 FNO                              .sup.1 H-NMR(CDCl.sub.3)δ: 0.95(6H, d,                              J=6.8 Hz), 1.8-2.1(1H, m), 2.93(2H,                              d, J=6.6 Hz), 6.11(1H, s), 6.55-6.75                              (2H, m), 6.9-7.5(6H, m)    H         OCH.sub.3                  oil C.sub.18 H.sub.23 NO:                              .sup.1 H-NMR(CDCl.sub.3)δ: 0.94(6H, d,                              J=6.6 Hz), 1.75-2.05(1H, m), 2.94                              (2H, d), 3.86(3H, s), 6.02(1H, s),                              6.5-6.75(2H, m), 6.85-7.0(3H, m),                              7.1-7.4(3H, m)    __________________________________________________________________________

                                      TABLE 21    __________________________________________________________________________     ##STR78##           m.p.       Elemental Analysis (Found)    X    Y (°C.)              Formula C   H   N    __________________________________________________________________________    H    Cl           oil              C.sub.23 H.sub.28 ClNO.sub.4                      .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.4(9H, m),                      1.9(1H, m), 2.6-4.5(4H, m), 6.1-7.7                      (11H, m)    (4)-CH.sub.3         Cl           oil              C.sub.24 H.sub.28 ClNO.sub.4                      .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.4(9H, m),                      1.8-3.2(5H, m), 4.0-4.5(3H, m),                      6.0-7.6(10H, m)    (4)-Cl         F oil              C.sub.23 H.sub.26 ClFNO.sub.4                      .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.4(9H, m),                      1.85(1H, m), 2.5-4.4(4H, m), 5.9-7.9                      (10H, m)    __________________________________________________________________________

                                      TABLE 22    __________________________________________________________________________                  m.p.        Elemental Analysis (Found)    X         Y   (°C.)                      Formula C     H    N    __________________________________________________________________________     ##STR79##              Cl  oil C.sub.28 H.sub.30 ClNO.sub.4                              .sup.1 H-NMR(CDCl.sub.3)δ: 0.7-1.4(9H,                              m), 1.8-2.3(3H, m), 2.7-3.2(5H, m), 4.0-4.5(3H,                              m), 5.95-7.7(9H, m),    H         F   oil C.sub.23 H.sub.28 FNO.sub.4                              .sup.1 H-NMR(CDCl.sub.3)δ: 0.75-1.15(6H,                              m),                              1.20(3H, t, J=7.0 Hz), 1.5-2.1 (1H, m),                              2.6-2.8, 2.95-3.15(1H, both m,), 4.0-                              4.5(3H, m), 6.0-6.5(2H, m), 6.7-                              7.8(9H, m)    H         OCH.sub.3                  oil C.sub.24 H.sub.29 NO.sub.5                              .sup.1 H-NMR (CDCl.sub.3)δ: 0.7-1.1(6H,                              m),                              1.20(3H,t, J=7.1 Hz), 1.7-2.0(1H, m),                              2.5-3.2(2H, m), 3.74, 3.78(3H, s),                              4.0-4.45(3H, m), 6.0-6.5(2H, m),                              6.7-7.85(9H, m)    __________________________________________________________________________

Example 5Trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In substantially the same manner as in Reference Example 4, ethyl esteroftrans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (2.0 g) obtained in Example 3 was subjected to hydrolysis to givetrans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (1.23 g) as prisms, m.p. 192° C.-195° C.

IRν_(max) ^(KBr) cm⁻¹ : 1735, 1650(C═O)

Elemental Analysis for C₂₂ H₂₅ NO₄ : Calcd.: C 71.91; H 6.66; N 3.81Found: C 71.86; H 6.78; N 3.80

Example 6

In substantially the same manner as in Reference Example 4, usingcompounds obtained in Example 4, compounds listed in Table 23 wereobtained.

                                      TABLE 23    __________________________________________________________________________     ##STR80##                 m.p.        Elemental Analysis (Found)    X        Y   (°C.)                      Formula                             C   H   N    __________________________________________________________________________    H        Cl  192-193                      C.sub.21 H.sub.22 ClNO.sub.4                             65.03                                 5.72                                     3.61                             (64.73)                                 (5.63)                                     (3.76)    (7)-CH.sub.3             Cl  166-167                      C.sub.22 H.sub.24 ClNO.sub.4                             65.75                                 6.02                                     3.49                             (65.78)                                 (6.02)                                     (3.72)    (7)-Cl   F   153-154                      C.sub.21 H.sub.21 ClFNO.sub.4                             62.15                                 5.22                                     3.45                             (62.17)                                 (5.19)                                     (3.50)     ##STR81##             Cl  170-171                      C.sub.24 H.sub.28 ClNO.sub.4                             66.66 (66.61)                                 6.18 (6.27)                                     3.24 (3.12)    H        F   185-187                      C.sub.21 H.sub.22 FNO.sub.4                             67.91                                 5.97                                     3.77                             (67.93)                                 (6.01)                                     (3.65)    H        OCH.sub.3                 243-245                      C.sub.22 H.sub.26 NO.sub.4                             68.91                                 6.57                                     3.65                             (68.89)                                 (6.60)                                     (3.74)    __________________________________________________________________________

Example 7Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid pivaloyloxymethyl ester

In N,N-dimethylformamide (10 ml) was dissolvedtrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.5 g) obtained in Example 2. To the solution were addedpivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52ml) and KI (0.2 g). The mixture was stirred at room temperatureovernight. To the reaction mixture were added water (100 ml) and ethylacetate (100 ml), followed by extraction. The ethyl acetate layer waswashed with an aqueous solution of potassium hydrogensulfate, an aqueoussolution of sodium hydrogencarbonate and water, successively, which wasdried over anhydrous magnesium sulfate. The solvent was then distilledoff under reduced pressure. The residue was purified by means of asilica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) toaffordtrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid pivaloyloxymethyl ester (0.55 g).

IRν_(max) ^(Neat) cm⁻¹ : 1750, 1675(C═O)

Elemental Analysis for C₂₇ H₃₁ Cl₂ NO₆ : Calcd.: C 60.45; H 5.82; N 2.61Found : C 60.38; H 5.93; N 2.48

Reference Example 7 Ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

(1) 5-Chloro-α-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzylalcohol

To a solution of 2-amino-5-chloro-α-(2-chloro phenyl)benzyl alcohol (5.0g) and 2,4-dimethoxy benzaldehyde (3.72 g) in acetic acid (50 ml) wasadded, under ice-cooling, sodium borohydride (0.94 g). The mixture wasstirred for one hour at room temperature, which was poured into water(200 ml), followed by extraction with ethyl acetate (200 ml×2). Theethyl acetate layer was washed with 1N sodium hydroxide, which was driedover anhydrous magnesium sulfate, followed by distilling off the solventunder reduced pressure. The residue was purified by means of a silicagel column chromatography (hexane:ethyl acetate=5:1) to give5-chloro-α-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzyl alcohol(7.5 g) as an oily product.

¹ H-NMR (CDCl₃) δ: 3.78(3H,s), 3.79(3H,s), 3.65-3.95(1H,m), 4.27(2H,s),6.15(1H,s), 6.35-7.55(10H,m)

(2) Ethyl ester of 3- N-4-chloro-2-(2-chloro-α-hydroxybenzyl)phenyl!-N-(2,4-dimethoxybenzyl)carbamoyl!acrylicacid

A solution of fumaric acid monoethyl ester (2.24 g) and thionyl chloride(3.4 ml) in toluene (10 ml) was stirred for 30 minutes at 90° C. Thenthe solvent was distilled off under reduced pressure to leave acidchloride of fumaric acid monoethyl ester. This product and5-chloro-α-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzyl alcohol(5.0 g) obtained in (1) were dissolved in methylene chloride (100 ml).To the solution was added sodium hydrogencarbonate (2.01 g), and themixture was stirred for 30 minutes at room temperature. The reactionmixture was washed with water and dried over anhydrous magnesiumsulfate, then the solvent was distilled off under reduced pressure. Theresidue was purified by means of a silica gel column chromatography(hexane:ethyl acetate=2:1) to give 3- N-4-chloro-2-(2-chloro-α-hydroxybenzyl)phenyl!-N-(2,4-dimethoxybenzyl)carbamoyl!acrylicacid ethyl ester (5.5 g) as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 3390(OH); 1720, 1610(C═O); 1655(C═C)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.2-1.4(3H,m), 3.4-3.9(6H,m),3.95-4.4(3H,m), 4.45-4.75(1H,m), 5.25-5.6(1H,m), 6.0-8.05(13H,m)

(3)Trans-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid ethyl ester

In ethanol (50 ml) was dissolved 3- N-4-chloro-2-(2-chloro-α-hydroxybenzyl)phenyl!-N-(2,4-dimethoxybenzyl)carbamoyl!acrylicacid ethyl ester (5.5 g) obtained in (2). To the solution was addedpotassium carbonate (1.4 g), and the mixture was stirred for 2 hours. Tothe reaction mixture were added water (200 ml) and ethyl acetate (300ml). The mixture was subjected to extraction. The ethyl acetate layerwas washed with water and dried over anhydrous magnesium sulfate, thenthe solvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography to affordtrans-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid ethyl ester as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1675(C═O)

Elemental Analysis for C₂₈ H₂₇ Cl₂ NO₆ : Calcd.: C 61.77; H 5.00; N 2.57Found : C 62.06; H 5.26; N 2.61

Reference Example 8Trans-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

To a solution oftrans-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid ethyl ester (1.0 g) obtained in Reference Example 7 in methanol (20ml) was added an aqueous solution (10 ml) of potassium carbonate (0.51g), followed by stirring for one hour at 60° C. The reaction mixture wasacidified with 1N hydrochloric acid (50 ml), which was subjected toextraction with ethyl acetate (100 ml). The ethyl acetate layer waswashed with water and dried over anhydrous magnesium sulfate, then thesolvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (hexane:ethylacetate=1:1˜hexane:methylene chloride:ethanol=5:5:1) to affordtrans-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.43 g) as a powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 1715, 1670(C═O)

Elemental Analysis for C₂₆ H₂₃ Cl₂ NO₆ : Calcd.: C 60.48; H 4.49; N 2.71Found : C 60.21; H 4.73; N 2.72

Example 8 Ethyl ester of1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

(1) 2-(5-Oxotetrahydrofuran-2-carbonyl)aminobenzophenone

A mixture of 4.9 g of 5-oxotetrahydrofuran-2-carboxylic acid and 5.5 mlof thionyl chloride was subjected to reflux for 2 hours. Thionylchloride was then distilled off under reduced pressure to leave5-oxotetrahydrofuran-2-carbonyl chloride. This product was mixed with5.0 g of 2-aminobenzophenone, 200 ml of ethyl acetate and 200 ml of asaturated aqueous solution of sodium hydrogencarbonate, which wasstirred for one hour at room temperature. The ethyl acetate layer waswashed with water and dried over anhydrous magnesium sulfate, then thesolvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent,hexane:ethyl acetate=2:1) to give2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone (6.5 g) as needles,m.p. 100° C.-102° C.

IRν_(max) ^(KBr) cm⁻¹ : 3300(NH), 1790, 1690, 1640(C═O)

Elemental Analysis for C₁₈ H₁₅ NO₄ : Calcd.: C 69.89; H 4.88; N 4.53Found : C 69.98; H 5.01; N 4.41

(2) 2- N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!aminobenzophenone

In 20 ml of N,N-dimethylformamide was dissolved 3.0 g of2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone obtained in (1). Tothe solution were added 1.73 ml of benzyl bromide, 2.67 g of potassiumcarbonate and 0.1 g of tetrabutyl ammonium iodide. The mixture wasstirred overnight at room temperature. The reaction mixture wassubjected to extraction with a mixture of 200 ml of ethyl acetate and100 ml of water. The ethyl acetate layer was washed with 0.1Nhydrochloric acid and an aqueous solution of sodium hydrogencarbonate,which was then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by meansof a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1)to give crystals. Recrystallization from hexane-ethyl acetate afforded2- N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!aminobenzophenone (3.71g) as needles, m.p. 142°-143° C.

IRν_(max) ^(KBr) cm⁻¹ : 1780, 1660, 1650(C═O)

Elemental Analysis for C₂₅ H₂₁ NO₄ : Calcd.: C 75.17; H 5.30; N 3.51Found : C 75.05; H 5.59; N 3.49

(3) 2- N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!aminobenzophenone

In 100 ml of ethanol was dissolved 5.0 g of 2-N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!aminobenzophenone obtainedin (2). To the solution was added 0.2 ml of conc. sulfuric acid, and themixture was left standing for 7 days. Ethanol was distilled off underreduced pressure. The residue was subjected to extraction with a mixtureof 100 ml of water and 200 ml of ethyl acetate. The ethyl acetate layerwas washed with an aqueous solution of sodium hydrogencarbonate, whichwas then dried over anhydrous magnesium sulfate. The solvent was thendistilled off under reduced pressure. The residue was purified by meansof a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1)to afford 2.8 g of 2- N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!aminobenzophenone as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 3440(OH), 1735, 1670(C═O)

Mass spectrum (m/e): 445 (M⁺)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.20(3H,t,J=7.2 Hz), 1.65-2.0(2H,m),2.2-2.6(2H,m), 3.65-3.7(1H,br), 4.05(2H,q,J=7.2 Hz), 4.0-4.35(1H,m),4.69(1H,d,J=14.4 Hz), 4.87(1H,d,J=14.4 Hz), 6.9-7.9(14H,m)

(4) 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!aminobenzophenone

2- N-Benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!aminobenzophenone (2.8g) obtained in (3) was dissolved in 30 ml of ethyl acetate. To thesolution were added, under ice-cooling, 0.73 ml of methanesulfonyloxychloride and 1.31 ml of triethylamine. The mixture was stirred for 2hours at room temperature. The reaction mixture was then washed with 1NHCl and an aqueous solution of sodium hydrogencarbonate, successively,which was dried over anhydrous magnesium sulfate, followed by distillingoff the solvent under reduced pressure. The residue was purified bymeans of a silica gel column chromatography (eluent, hexane:ethylacetate=2:1) to afford 3.2 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!aminobenzophenoneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1670(C═O)

Mass spectrum (m/e): 523 (M⁺)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.1-1.35(3H,m), 2.0-2.6(4H,m),3.14+3.38(3H,each s), 3.9-4.7(3H,m), 4.93(d,J=14.2 Hz)+5.53(d,J=14.8Hz)(1H), 5.05-5.15(m)5.15-5.3(m)(1H), 7.0-7.85(14H,m)

(5)Ethyl-cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionateandethyl-trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionate

In 30 ml of ethanol was dissolved 3.2 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!aminobenzophenone obtained in (4). To the solution was added,under ice-cooling, 0.32 g of sodium borohydride. The reaction mixturewas stirred for 45 minutes at 50° C., followed by cooling the reactionmixture to room temperature. The reaction mixture was acidified by theaddition of 100 ml of 1N HCl, which was subjected to extraction with 200ml of ethyl acetate. The extract solution was washed with an aqueoussolution of sodium hydrogencarbonate, dried over magnesium sulfate, thenthe solvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent,hexane:ethyl acetate=10:1 to 5:1) to afford, as the first fraction, 0.73g of ethyl ester ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as needles, m.p. 107° C.-108° C.

IRν_(max) ^(KBr) cm⁻¹ : 1735, 1670(C═O)

Elemental Analysis for C₂₇ H₂₇ NO₄ : Calcd.: C 75.50; H 6.34; N 3.26Found: C 75.21; H 6.44; N 3.27

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.21(3H,t,J=7.2 Hz), 2.2-2.4(2H,m),2.55(2H,t,J=7.0 Hz), 3.72(1H,d,J=16.0 Hz), 4.10(2H,q,J=7.2 Hz),4.23(1H,t,J=6.5 Hz), 4.70(1H,d,J=16.0 Hz), 5.95(1H,s), 7.0-7.5(14H,m)

As the second fraction, 0.3 g of ethyl ester oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1670(C═O)

Mass spectrum (m/e): 429 (M⁺)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.17(3H,t,J=7.1 Hz), 2.05-2.4(2H,m),2.49(2H,t,J=7.0 Hz), 4.06(2H,q,J=7.1 Hz), 3.95-4.05(1H,m),4.86(1H,d,J=14.6 Hz), 5.46(1H,s), 5.50(1H,d,J=14.6 Hz), 6.53(1H,d,J=7.8Hz), 7.0-7.45(13H,m)

Example 9 Ethyl ester ofcis-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

(1) 2',5-Dichloro-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenone

In substantially the same manner as in Example 8 (1), 15 g of2-amino-2',5-dichlorobenzophenone was allowed to react with5-oxotetrahydrofuran-2-carbonyl chloride to afford 18.1 g of2',5-dichloro-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenone,m.p. 170° C.-173° C.

IRν_(max) ^(KBr) cm⁻¹ : 3250(NH), 1775, 1695, 1640(C═O)

Elemental Analysis for C₁₈ H₁₃ Cl₂ NO₄ : Calcd.: C 57.16; H 3.46; N 3.70Found: C 57.29; H 3.55; N 3.57

(2) 2-N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!amino-2',5-dichlorobenzophenone

In substantially the same manner as in Example 8 (2), 20 g of2',5-dichloro-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenoneobtained in (1) was allowed to react with benzyl bromide to afford 24.5g of 2-N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!amino-2',5-dichlorobenzophenoneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1780, 1670(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.1-2.55(2H,m), 2.65-3.0(2H,m),4.01(d,J=14.4 Hz)+4.29(d,J=14.4 Hz)(1H), 4.75-4.9(1H,m), 5.29(d=14.4Hz)+5.47(d,J=14.4 Hz)(1H), 6.6-7.6(13H,m)

(3) 2- N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!amino-2',5-dichlorobenzophenone

23 g of 2-N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!amino-2'5-dichlorobenzophenoneobtained in (2) was subjected to substantially the same reaction as inExample 8 (3) to afford 17 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!amino-2',5-dichlorobenzophenone.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1660(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.1-1.35(3H,m), 1.6-2.0(2H,m),2.3-2.8(2H,m), 3.9-4.8(4H,m), 5.34(d,J=14.4 Hz)+5.69(d,J=14.4 Hz)(1H),6.8-7.6(12H,m)

(4) 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!amino-2',5-dichlorobenzophenone

In substantially the same manner as in Example 8 (4), 17 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!amino-2',5-dichlorobenzophenone was allowed to react withmethanesulfonyl chloride to afford 19 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!amino-2',5-dichlorobenzophenoneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : =1730, 1675(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.1-1.35(3H,m), 1.9-2.6(4H,m),3.17+3.32(3H,each s), 4.85-5.0(m)+5.05-5.15(m)(1H), 5.45(d,J=14.4Hz)+5.72(d,J=14.4 Hz)(1H), 6.9-7.6(12H,m)

(5) Ethyl ester ofcis-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid and ethyl ester oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

19 g of 2- N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!amino-2',5-dichlorobenzophenone was subjected tosubstantially the same reaction as in Example 8 (5). The reactionmixture was purified by means of a silica gel column chromatography. Asthe first fraction, 3.1 g of ethyl ester ofcis-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid was obtained in the form of an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1670(C═O)

As the second fraction, 3.3 g of ethyl ester oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as prisms, m.p. 122° C.-123° C.

IRν_(max) ^(Neat) cm⁻¹ : 1740,1670(C═O)

Elemental Analysis for C₂₇ H₂₅ Cl₂ NO₄ : Calcd.: C 65.07; H 5.06; N 2.81Found: C 65.30; H 5.09; N 2.81

Example 10 Ethyl ester of7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

(1) 2',5-Dichloro-2-N-methyl-N-(5-oxotetrahydrofuran-2-carbonyl)!aminobenzophenone

In 100 ml of acetone was dissolved 15 g of2',5-dichloro-2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenoneobtained in Example 9 (1). To the solution were added 4.96 ml of methyliodide and 11 g of potassium carbonate, and the mixture was stirred for3 days at room temperature. The reaction mixture was subjected todistillation under reduced pressure. The residue was subjected toextraction by the addition of 200 ml of water and 300 ml of ethylacetate. The ethyl acetate layer was washed with water and dried overanhydrous magnesium sulfate, then the solvent was distilled off underreduced pressure. The residue was purified by means of a silica gelchromatography (eluent, hexane:ethyl acetate=2:1 to 1:1) to afford 13.5g of 2',5-dichloro-2-N-methyl-N-(5-oxotetrahydrofuran-2-carbonyl)!aminobenzophenone as anoily product.

IRν_(max) ^(Neat) cm⁻¹ : 1780,1675(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ2.1-3.0(4H,m), 3.08+3.14(3H,each s),4.75-4.9(1H,m), 7.1-7.7(7H,m)

(2) 2',5-Dichloro-2- N-(4-ethoxycarbonyl-2-hydroxy)butyryl-N-methyl!aminobenzophenone

13.5 g of 2',5-dichloro-2- N-methyl-N-(5-oxotetrahydrofuran-2-carbonyl)!aminobenzophenone was subjected to substantially thesame reaction as in Example 8 (3) to afford 9.5 g of 2',5-dichloro-2-N-(4-ethoxycarbonyl-2-hydroxy)butyryl-N-methyl!aminobenzophenone as anoily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1670, 1660(C═O)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 1.1-1.4(3H,m), 1.5-1.9(2H,m),2.0-2.75(2H,m), 3.0-3.5(3H,m), 3.95-4.5(4H,m), 7.2-7.7(7H,)

(3) 2',5-Dichloro-2-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl-N-methyl!aminobenzophenone

In substantially the same manner as in Example 8 (4), 9.5 g of2',5-dichloro-2-N-(4-ethoxycarbonyl-2-hydroxy)butyryl-N-methyl!aminobenzophenoneobtained in (2) was allowed to react with methanesulfonyl chloride togive 11.0 g of 2',5-dichloro-2-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl-N-methyl!aminobenzophenoneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1680(C═O)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 1.1-1.35(3H,m), 1.9-2.7(4H,m),3.0-3.7(6H,m), 3.9-4.25(2H,m), 4.9-5.7(1H,m), 7.3-7.75(7H,m)

(4) Ethyl ester of7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

11.0 g of 2',5-dichloro-2-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl-N-methyl!aminobenzophenoneobtained in (3) was subjected to substantially the same reaction inExample 8 (5), and the reaction product was purified by means of asilica gel column chromatography to give 4.17 g of the mixture of cis-and trans-isomers of ethyl ester of7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1735, 1675(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.19(3H,t,J=7.2 Hz), 1.21(3H,t,J=7.2Hz), 2.0-2.4(4H,m), 2.4-2.6(4H,m), 3.15(3H,s), 3.51(3H,s),3.95-4.2(5H,m), 4.36(1H,t,J=6.6 Hz), 5.99(1H,s), 6.16(1H,s),6.50(1H,d,J=2.4 Hz), 7.05-7.8(13H,m)

Example 11 Ethyl ester of1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid (1) 4'-Methoxy-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenone

In substantially the same manner as in Example 8 (1), 8 g of2-amino-4'-methoxybenzophenone was allowed to react with5-oxotetrahydrofuran-2-carbonyl chloride to give 12 g of4'-methoxy-2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone as anoily product.

IRν_(max) ^(Neat) cm⁻¹ : 1780, 1685, 1625(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.3-2.8(4H,m), 3.89(3H,s),4.9-5.05(1H,m), 6.9-7.85(7H,m), 8.5-8.6(1H,m), 11.2(1H,br)

(2) 2-N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!amino-4'-methoxybenzophenone

In substantially the same manner as in Example 8 (2), 12 g of4'-methoxy-2-(5-oxotetrahydrofuran-2-carbonyl) aminobenzophenoneobtained in (1) was allowed to react with benzyl bromide to give 13.2 gof 2N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!amino-4'-methoxybenzo-phenoneas prisms, m.p. 137° C.-138° C.

IRν_(max) ^(KBr) cm⁻¹ : 1775, 1660, 1645(C═O)

Elemental Analysis for C₂₆ H₂₃ NO₅ : Calcd.: C 72.71; H 5.40; N 3.26Found: C 72.98; H 5.46; N 3.22

(3) 2- N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!amino-4'-methoxybenzophenone

13.0 g of 2-N-benzyl-N-(5-oxotetrahydrofuran-2-carbonyl)!amino-4'-methoxybenzophenoneobtained in (2) was subjected to substantially the same reaction as inExample 8 (3) to give 10.5 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!amino-4'-methoxybenzophenoneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1650(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.1-1.35(3H,m), 1.7-2.1(2H,m),2.2-2.55(2H,m), 3.88(3H,s), 3.9-4.3(3H,m), 4.52(1H,d,J=14.4 Hz),4.99(1H,d,J=14.4 Hz), 6.8-7.9(13H,m)

(4) 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!amino-4'-methoxybenzophenone

In substantially the same manner as in Example 8 (4), 10.5 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-hydroxy)butyryl!amino-4'-methoxybenzophenone was allowed to react withmethanesulfonyl chloride to give 8.5 g of 2-N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!amino-4'-methoxybenzophenoneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1670, 1660(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.1-1.3(3H,m), 2.0-2.6(4H,m),3.14+3.38(3H,each s), 3.89+3.91(3H,each s), 3.9-4.6(3H,m),4.9-5.65(2H,m), 6.8-7.9(13H,m)

(5) Ethyl ester ofcis-1-benzyl-5-(4-methoxyphenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid and ethyl ester oftrans-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

8.5 g of 2- N-benzyl-N-(4-ethoxycarbonyl-2-methanesulfonyloxy)butyryl!amino-4'-methoxybenzophenone obtained in (4) was subjected tosubstantially the same reaction as in Example 8 (5) to give a mixtureproduct, which was purified by means of a silica gel columnchromatography to give, as the first fraction, 2.0 g of ethyl ester ofcis-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as needles, m.p. 95°-96° C.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1670(C═O)

Elemental Analysis for C₂₈ H₂₉ NO5: Calcd.: C 73.18; H 6.36; N 3.05Found: C 73.09; H 6.42; N 3.19

As the second fraction, 0.88 g of ethyl ester oftrans-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetra-hydro-4,1-benzoxazepine-3-propionicacid was obtained as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1670(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.17(3H,t,J=7.1 Hz), 2.1-2.4(2H,m),2.47(2H,t,J=7.1 Hz), 3.82(1H,s), 3.95-4.2(3H,m), 4.87(1H,d,J=14.6 Hz),5.42(1H,s), 6.58(1H,d,J=7.2 Hz), 6.8-7.5(12H,m)

Example 12 methyl ester of1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid (I) 2-N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl!aminobenzophenone

A mixture of 7.6 g of 2-chloro-4-methoxycarbonyl valeric acid, 9.2 ml ofthionyl chloride and 30 ml of toluene was stirred for 30 minutes at 80°C., followed by distilling off the solvent under reduced pressure toleave 2-chloro-4-methoxycarbonyl butyryl chloride. A mixture of thiscompound, 5.0 g of 2-benzylaminobenzophenone, 100 ml of ethyl acetateand 100 ml of a saturated aqueous solution of sodium hydrogencarbonatewas stirred for 30 minutes at room temperature. The ethyl acetate layerwas washed with water and dried over anhydrous magnesium sulfate, thenthe solvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent,hexane:ethyl acetate=5:1) to give 1.2 g of 2-N-benzyl-N-(2-chloro-4-methoxy carbonyl)butyryl!aminobenzophenone as anoily product.

IRν_(max) ^(Neat) cm⁻¹ : 1735, 1655(C═O)

Mass spectrum (m/e): 449 (M⁺)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.3-2.8(4H,m), 3.62(3H,s),4.2-4.3(1H,m), 4.53(1H,d,J=14.4 Hz), 4.92(1H,d,J=14.4 Hz),6.9-7.75(14H,m)

(2) 2- N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl! aminodiphenylmethanol

Method A!

In 30 ml of methanol was dissolved 1.2 g of 2-N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl!amino benzophenone. Tothe solution was added, under ice-cooling, 0.135 g of sodiumborohydride. The mixture was stirred for 30 minutes at room temperature,then the solvent was distilled off under reduced pressure. To theresidue was added 100 ml of 1N hydrochloric acid to make the solutionacid, which was subjected to extraction with 100 ml of ethyl acetate.The ethyl acetate layer was washed with an aqueous solution of sodiumhydrogencarbonate and dried over anhydrous magnesium sulfate, then thesolvent was distilled off. The residue was purified by means of a silicagel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 1.1g of 2- N-benzyl-N-(2-chloro-4-methoxycarbonyl) butyryl!aminodiphenylmethanol.

IRν_(max) ^(Neat) cm⁻¹ : 3430(OH), 1735, 1660(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.95-2.65(4H,m), 3.2-4.4(6H,m),5.1-5.5(1H,m), 5.75-6.15(1H,m), 6.5-7.85(14H,m)

Method B!

A mixture of 6.2 g of 2-chloro-4-methoxycarbonyl valeric acid and 12.6ml of thionyl chloride was refluxed for 30 minutes, then the solvent wasdistilled off under reduced pressure to leave 2-chloro-4-methoxycarbonylbutyryl chloride. A mixture of this product, 5.0 g of2-benzylaminodiphenyl methanol, 100 ml of ethyl acetate and 100 ml of asaturated aqueous solution of sodium hydrogencarbonate was stirred forone hour at room temperature. The ethyl acetate layer was washed withwater and dried over anhydrous magnesium sulfate. then the solvent wasdistilled off under reduced pressure. The residue was purified by meansof a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1)to give 5.3 g of 2-N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl!amino-diphenyl methanolas an oily product.

(3) Methyl ester ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid and methyl ester oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In 20 ml of tetrahydrofuran was dissolved 1.1 g of 2-N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl!aminodiphenyl methanol.To the solution was added 107 mg of sodium hydride (60% in oil), and themixture was stirred for one hour at room temperature. To the reactionmixture was added 50 ml of 1N hydrochloric acid to make the solutionacid, which was subjected to extraction with 100 ml of ethyl acetate.The ethyl acetate layer was washed with an aqueous solution of sodiumhydrogencarbonate and dried over anhydrous magnesium sulfate, then thesolvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent,hexane:ethyl acetate=5:1). From the first fraction, 0.4 g of methylester ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as plates, m.p. 134°-136° C.

IRν_(max) ^(KBr) cm⁻¹ : 1740, 1670(C═O)

Elemental Analysis for C₂₅ H₂₅ NO₄ : Calcd.: C 75.16; H 6.06; N 3.37Found: C 74.74; H 5.97; N 3.38

From the second fraction, 0.18 g of methyl ester oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid was obtained as needles, m.p. 116°-118° C.

IRν_(max) ^(KBr) cm⁻¹ : 1740, 1670(C═O)

Elemental Analysis for C₂₆ H₂₅ NO₄ : Calcd.: C 75.16; H 6.06; N 3.73Found: C 75.22; H 5.94; N 3.58

Example 13Cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In 20 ml of methanol was dissolved 0.5 g of ethyl ester ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 8. To the solution was added 7 ml of 1N sodiumhydroxide, and the mixture was stirred for 30 minutes at roomtemperature. The reaction mixture was acidified with 100 ml of INhydrochloric acid, which was subjected to extraction with 150 ml ofethyl acetate. The ethyl acetate layer was washed with water and driedover anhydrous magnesium sulfate. Then the solvent was distilled offunder reduced pressure to leave 0.46 g ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as plates, m.p. 112°-114° C.

IRν_(max) ^(KBr) cm⁻¹ : 1710, 1670(C═O)

Elemental Analysis for C₂₅ H₂₃ NO₄ : Calcd.: C 74.80; H 5.77; N 3.49Found: C 74.52; H 5.85; N 4.42

Example 14Trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In substantially the same manner as in Example 13, 1.0 g of ethyl esteroftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 8 was subjected to hydrolysis to give 0.81 g oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as plates, m.p. 148°-150° C.

IRν_(max) ^(KBr) cm⁻¹ : 1735, 1650(C═O)

Elemental Analysis for C₂₅ H₂₃ NO₄ : Calcd.: C 74.80; H 5.77; N 3.49Found: C 74.66; H 5.78; N 3.55

In substantially the same manner as above, 0.9 g of methyl ester oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 12 was subjected to hydrolysis to give 0.86 goftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid.

Example 15Cis-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In substantially the same manner as in Example 13, 3.1 g of ethyl esterofcis-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 9 was subjected to hydrolysis to give 2.9 g ofcis-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as prisms, m.p. 135°-137° C.

IRν_(max) ^(KBr) cm⁻¹ : 1725, 1640(C═O)

Elemental Analysis for C₂₅ H₂₁ Cl₂ NO₄ : Calcd.: C 63.84; H 4.50; N 2.98Found: C 64.02; H 4.76; N 2.88

Example 16Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In substantially the same manner as in Example 13, 2.7 g of ethyl esteroftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 9 was subjected to hydrolysis to give 2.5 gtrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as prisms, m.p. 192°-194° C.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1640(C═O)

Elemental Analysis for C₂₅ H₂₁ Cl₂ NO₄ : Calcd.: C 63.84; H 4.50; N 2.98Found: C 63.99; H 4.57; N 2.92

Example 177-Chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In substantially the same manner as in Example 13 4.1 g of ethyl esterof7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 10 was subjected to hydrolysis to give 3.7 g of7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as an oily product of the mixture of cis- and trans-compounds(1:1).

IRν_(max) ^(Neat) cm⁻¹ : 1705, 1670(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.0-2.4(4H,m), 2.45-2.7(4H,m),3.14(3H,s), 3.50(3H,s), 4.00(1H,dd,J=7.2×5.4 Hz), 4.35(1H,t,J=6.7 Hz),5.99(1H,s), 6.16(1H,s), 6.50(1H,d,J=2.2 Hz), 7.0-7.81(13H,m)

Example 18Cis-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In substantially the same manner as in Example 13 1.7 g of ethyl esterofcis-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 11 was subjected to hydrolysis to give 1.5 g ofcis-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as prisms, m.p. 107° C.-109° C.

IRν_(max) ^(KBr) cm⁻¹ : 1715, 1670(C═O)

Elemental Analysis for C₂₆ H₂₅ NO₅ : Calcd.: C 72.37; H 5.84; N 3.25Found: C 72.26; H 5.90; N 3.10

Example 19Trans-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid

In substantially the same manner as in Example 13 0.85 g of ethyl esteroftrans-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid was subjected to hydrolysis to give 0.78 g oftrans-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1710, 1670(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.05-2.35(2H,m), 2.52(2H,t,J=7.1Hz), 3.81(1H,s), 4.00(1H,dd,J=7.3×5.7 Hz), 4.39(1H,d,J=14.4 Hz),5.40(1H,s), 5.49(1H,d,J=14.4 Hz), 6.57(1H,d,J=7.2 Hz), 6.8-7.5(12H,m)

Example 20Trans-1-benzyl-3-(3-hydroxypropyl)-5-phenyl-1,5-dihydro-4,1-benzoxazepine-2(3H)-one

The mixture of 0.4 g of methyl ester oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 12, 0.16 g of sodium borohydride and 0.16 g oflithium chloride in 15 ml of tetrahydrofuran were stirred for 10 minutesat room temperature. To the resultant was added 30 ml of ethanol, whichwas stirred for 2 hours at 60° C. To the reaction mixture were added 100ml of 1N hydrochloric acid and 150 ml of ethyl acetate. The ethylacetate layer was washed with an aqueous solution of sodiumhydrogencarbonate, which was dried over anhydrous magnesium sulfate,then the solvent was distilled off under reduced pressure. The residuewas purified by means of a silica gel column chromatography (eluent,hexane:ethyl acetate=2:1) to give 0.19 g oftrans-1-benzyl-3-(3-hydroxypropyl)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-oneas needles, m.p. 59°-62° C.

IRν_(max) ^(KBr) cm⁻¹ : 1645 (C═O)

Elemental Analysis for C₂₅ H₂₅ NO₃ : Calcd.: C 77.49; H 6.50; N 3.61Found: C 77.12; H 6.44; N 3.87

Example 21Cis-1-benzyl-3-(3-3-hydroxypropyl)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one

In substantially the same manner as in Example 20, 0.23 g of methylester ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 12 was subjected to reduction to give 0.09 g ofcis-1-benzyl-3-(3-hydroxypropyl)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-oneas needles, m.p. 94°-95° C.

IRν_(max) ^(KBr) cm⁻¹ : 1675, 1660(C═O)

Elemental Analysis for C₂₅ H₂₅ NO₃ : Calcd.: C 77.49; H 6.50; N 3.61Found: C 77.44; H 6.49; N 3.76

Example 22N-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)aminoethanol

In 5 ml of N,N-dimethylformamide were dissolved 0.3 g ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 13 and 0.054 ml of ethanolamine. To thesolution were added, under ice-cooling, 0.17 g of diethylphosphorocyanidate and 0.14 ml of triethylamine. The mixture was stirredfor 30 minutes at room temperature, to which was added 100 ml of water.The mixture was subjected to extraction with ethyl acetate (100 ml×2).The ethyl acetate layer was washed with 1N hydrochloric acid and anaqueous solution of sodium hydrogencarbonate, successively, which wasthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by means of asilica gel column chromatography (eluent, hexane: methylenechloride:ethanol=5:5:1) to give 0.28 g ofN-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)aminoethanolas needles, m.p. 117°-119° C.

IRν_(max) ^(KBr) cm⁻¹ : 1670, 1640(C═O)

Elemental Analysis for C₂₇ H₂₈ N₂ O₄. 0.5H₂ O: Calcd.: C 71.50; H 6.44;N 6.18 Found: C 71.29; H 6.47; N 5.98

Example 23N-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)aminoethanol

In substantially the same manner as in Example 22 0.25 g oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 14 was subjected to condensation withethanolamine to give 0.20 g ofN-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)aminoethanolas plates, m.p. 125° C.-127° C.

IRν_(max) ^(KBr) cm⁻¹ : 1675, 1645(C═O)

Elemental Analysis for C₂₇ H₂₈ N₂ O₄ : Calcd.: C 72.95; H 6.35; N 6.30Found: C 72.70; H 6.36; N 6.19

Example 24 Methyl ester ofN-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophane

In 10 ml of N,N-dimethylformamide were dissolved 0.35 g ofcis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 13 and 0.23 g of L-tryptophane methyl esterhydrochloride. To the solution were added, under ice-cooling, 0.15 g ofdiethyl phosphorocyanidate and 0.24 ml of triethylamine. The mixture wasstirred for 30 minutes at room temperature, which was subjected toextraction with the addition of 100 ml of water and 100 ml of ethylacetate. The ethyl acetate layer was washed with 1N hydrochloric acidand an aqueous solution of sodium hydrogencarbonate, successively, whichwas then dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the residue was purified by means of a silica gelcolumn chromatography (eluent, hexane:ethyl acetate=1:1) to give 0.50 gof methyl ester ofN-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophaneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1740, 1665(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.15-2.5(4H,m), 3.27(2H,t,J=4.7 Hz),3.62+3.63(3H,each s), 3.71(1H,d,J=16.0 Hz), 4.15-4.3(1H,m),4.68(1H,d,J=16.0 Hz), 4.8-5.0(1H,m), 5.85(1H,s), 6.15-6.35(1H,m),6.9-7.6(19H,m), 8.13(1H,br)

Example 25N-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophane

In 10 ml of methanol was dissolved 0.5 g of methyl ester ofN-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophaneobtained in Example 24. To the solution was added 5 ml of 1N sodiumhydroxide, and the mixture was stirred for one hour at room temperature.The reaction mixture was made acid by the addition of 100 ml of 1Nhydrochloric acid, which was subjected to extraction with 100 ml ofethyl acetate. The ethyl acetate layer was washed with water and driedover anhydrous magnesium sulfate. The solvent was then distilled offunder reduced pressure to give 0.24 g ofN-(cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophaneas a powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1660(C═O)

Elemental Analysis for C₃₆ H₃₃ N₃ O₅ Calcd.: C 73.58; H 5.66; N 7.15Found C 73.56; H 6.07; N 6.79

Example 26 Methyl ester ofN-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophane

In substantially the same manner as in Example 24, 0.2 g oftrans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 14 was subjected to condensation withL-tryptophane methyl ester hydrochloride to give 0.28 g of methyl esterofN-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophaneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1740,1670(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.1-2.4(4H,m), 3.15-3.3(2H,m),3.6-3.7(3H,m), 3.95-4.15(1H,m), 4.8-5.0(2H,m), 5.45(1H,s),5.49(1H,d,J=14.2 Hz), 6.05-6.2(1H,m), 6.45-6.6(1H,m), 6.9-7.6(18H,m),8.03(1H,br)

Example 27N-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophane

In substantially the same manner as in Example 25, 0.28 g of methylester ofN-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophaneobtained in Example 26 was subjected to hydrolysis to give 0.24 g ofN-(trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl)-L-tryptophaneas a powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1660(C═O)

Elemental Analysis for C₃₆ H₃₃ N₃ O₅. 0.4H₂ O: Calcd.: C 72.69; H 5.73;N 7.06 Found C 72.82; H 5.84; N 6.79

Example 28 Methyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-L-tryptophane

In substantially the same manner as in Example 24, 0.3 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-2-propionicacid obtained in Example 16 was subjected to condensation withL-tryptophane methyl ester hydrochloride to give 0.41 g of methyl esterof N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-L-tryptophaneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1735, 1660(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.1-2.45(4H,m), 3.2-3.35(2H,m),3.64+3.66(3H,each s), 3.95-4.15(1H,m), 4.65-4.8(1H,m), 4.8-5.0(1H,m),5.5-5.65(1H,m), 5.76(1H,s), 6.0-6.2(1H,m), 6.35-6.45(1H,m),6.9-7.7(16H,m), 8.16(1H,br)

Example 29 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-L-tryptophane

In substantially the same manner as in Example 25, methyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-L-tryptophane(0.41 g) obtained in Example 28 was subjected to hydrolysis to give 0.31g of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-L-tryptophaneas a powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1660(C═O)

Elemental Analysis for C₃₆ H₃₁ Cl₂ N₃ O₅ : Calcd.: C 65.86; H 4.76; N6.40 Found: C 66.13; H 5.02; N 6.24

Example 30 Ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-D-tryptophane

In substantially the same manner as in Example 24, 0.3 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionicacid obtained in Example 16 was subjected to condensation withD-tryptophane ethyl ester hydrochloride to give 0.43 g of ethyl ester ofN-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-D-tryptophaneas an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1730, 1665(C═O)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.1-1.3(3H,m), 2.1-2.45(4H,m),3.2-3.35(2H,m), 3.95-4.2(3H,m), 4.65-4,8(1H,m), 4.8-5.0(1H,m),5.5-5.65(1H,m), 5.76(1H,s), 6.0-6.2(1H,m), 6.35-6.45(1H,m),6.9-7.7(16H,m), 8.13(1H,br)

Example 31 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-D-tryptophane

In substantially the same manner as in Example 25, 0.43 g of ethyl esterof N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-D-tryptophaneobtained in Example 30 was subjected to hydrolysis to give 0.38 g of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionyl!-D-tryptophaneas a powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 1725, 1660(C═O)

Elemental Analysis for C₃₆ H₃₁ Cl₂ N₃ O₅ : Calcd.: C 65.86; H 4.76; N6.40 Found: C 65.90; H 5.15; N 6.03

Example 32 Methyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylacetyl!-L-tryptophane

To a mixture of 0.6 g oftrans-7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Reference Example 4, 0.42 g of tryptophane methyl esterhydrochloride and 10 ml of dimethylformamide was added, while stirringunder ice-cooling, 0.3 g of diethyl phosphorocyanidate. To the resultantwas then added 0.55 ml of triethylamine. The reaction mixture wasstirred for 40 minutes at room temperature, which was poured intoice-water, followed by subjecting the mixture to extraction with ethylacetate. The organic layer was washed with a dilute aqueous solution ofpotassium hydrogensulfate, an aqueous solution of sodiumhydrogencarbonate and water, successively, dried and concentrated underreduced pressure. The concentrate was purified by means of a silica gelcolumn chromatography (eluent, hexane:ethyl acetate=1:1 to 1:3). Fromthe first fraction of the eluate, 0.33 g of methyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetyl!tryptophane of a crystalline form was obtained, m.p. 236° C.-237°C.

Elemental Analysis for C₃₀ H₂₇ Cl₂ N₃ O₅ : Calcd.: C 62.08; H 4.69; N7.24 Found: C 61.82; H 4.71; N 6.95

From the subsequent fraction of the eluate, 0.28 g of the steric isomerof the above compound was obtained, m.p. 159° C.-160° C.

Elemental Analysis for C₃₀ H₂₇ Cl₂ N₃ O₅ : Calcd.: C 62.08; H 4.69; N7.24 Found: C 61.94; H 4.50; N 6.96

Example 33

In substantially the same manner as in Example 32, compounds shown inTable 24 through Table 28 were obtained by using the compounds inReference Example 5 and Example 2.

                                      TABLE 24    __________________________________________________________________________    compd.                      m.p.            Elemental Analysis (Found)    No. R.sub.1   R.sub.2       (°C.)                                      Formula   C   H   N    __________________________________________________________________________         ##STR82##                  NHCH.sub.2 COOC.sub.2 H.sub.5                                153-155                                      C.sub.28 H.sub.28 Cl.sub.2 N.sub.2                                      O.sub.5   62.11 (62.05)                                                    4.84 (4.65)                                                        5.17 (4.98)    2         ##STR83##                  NH(CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                130-131                                      C.sub.28 H.sub.28 Cl.sub.2 N.sub.2                                      O.sub.5   62.71 (63.00)                                                    5.08 (5.03)                                                        5.04 (4.99)    3         ##STR84##                   ##STR85##    amorphous solid                                      C.sub.36 H.sub.31 Cl.sub.2 N.sub.3                                      O.sub.5. H.sub.2 O                                                64.10 (64.32)                                                    4.93 (4.78)                                                        6.23 (6.07)    4         ##STR86##                  Trp.OMe       amorphous solid                                      C.sub.38 H.sub.31 Cl.sub.2 N.sub.3                                      O.sub.6. 5/4H.sub.2 O                                                63.67 (63.94)                                                    4.97 (4.84)                                                        6.19 (5.90)    5         ##STR87##                  D-Trp.OMe     amorphous solid                                      C.sub.36 H.sub.31 Cl.sub.2 N.sub.3                                      O.sub.5. 1/2C.sub.4 H.sub.8 O.sub.2.1/2H                                      .sub.2 O  60.10 (60.11)                                                    4.88 (4.89)                                                        6.78 (6.69)    __________________________________________________________________________

                                      TABLE 25    __________________________________________________________________________    compd.                    m.p.            Elemental Analysis (Found)    No. R.sub.1   R.sub.2     (°C.)                                    Formula   C   H   N    __________________________________________________________________________         ##STR88##                  D-Trp.OMe   amorphous solid                                    C.sub.36 H.sub.31 Cl.sub.2 N.sub.3                                    O.sub.5. 1/2C.sub.4 H.sub.8 O.sub.2.1/4H.s                                    ub.2 O    60.53 (60.44)                                                  4.84 (4.85)                                                      6.83 (6.83)    7         ##STR89##                   ##STR90##  amorphous solid                                    C.sub.35 H.sub.32 Cl.sub.2 N.sub.2                                    O.sub.5. 1/4H.sub.2 O                                              66.09 (66.10)                                                  5.15 (5.15)                                                      4.41 (4.17)    8         ##STR91##                  Phe.OEt     amorphous solid                                    C.sub.35 H.sub.32 Cl.sub.3 N.sub.2                                    O.sub.5. 1/4H.sub.2 O                                              66.09 (66.20)                                                  5.15 (5.15)                                                      4.41 (4.17)    9         ##STR92##                  D-Phe.OMe   amorphous solid                                    C.sub.34 H.sub.30 Cl.sub.2 N.sub.2                                    O.sub.5. 1/4H.sub.2 O                                              65.65 (65.62)                                                  4.94 (5.17)                                                      4.50 (4.51)    10         ##STR93##                  D-Phe.OMe   amorphous solid                                    C.sub.34 H.sub.30 Cl.sub.2 N.sub.2                                    O.sub.5. 1/4H.sub.2 O                                              65.65 (65.48)                                                  4.94 (5.22)                                                      4.50 (4.31)    __________________________________________________________________________

                                      TABLE 26    __________________________________________________________________________    compd.                    m.p.          Elemental Analysis (Found)    No. R.sub.1   R.sub.2     (°C.)                                    Formula C   H   N    __________________________________________________________________________    11         ##STR94##                   ##STR95##  164-165                                    C.sub.35 H.sub.32 Cl.sub.2 N.sub.2                                    O.sub.5. 1/4H.sub.2 O                                            66.08 (66.18)                                                5.17 (5.44)                                                    4.40 (4.13)    12         ##STR96##                   ##STR97##  amorphous solid                                    C.sub.37 H.sub.33 Cl.sub.2 N.sub.3                                    O.sub.5. 2.5H.sub.2 O                                            62.10 (62.32)                                                5.35 (5.18)                                                    5.87 (5.63)    13  C.sub.2 H.sub.5                  NHCH.sub.2 COOC.sub.2 H.sub.5                              175-176                                    C.sub.23 H.sub.21 Cl.sub.2 N.sub.2                                    O.sub.5 57.63 (57.29)                                                5.05 (4.94)                                                    5.84 (5.90)    14  (CH.sub.2).sub.8 CH.sub.3                  NHCH.sub.2 COOC.sub.2 H.sub.5                              160-161                                    C.sub.28 H.sub.34 Cl.sub.2 N.sub.2                                    O.sub.5 61.20 (61.47)                                                6.24 (6.23)                                                    5.10 (5.39)    15  CH.sub.2 CH(CH.sub.3).sub.2                  NHCH.sub.2 COOC.sub.2 H.sub.5                              168-170                                    C.sub.25 H.sub.28 Cl.sub.2 N.sub.2                                    O.sub.5 59.18 (58.97)                                                5.56 (5.65)                                                    5.52 (5.40)    16         ##STR98##                  NHCH.sub.2 COOC.sub.2 H.sub.5                              206-207                                    C.sub.28 H.sub.28 Cl.sub.2 N.sub.2                                    O.sub.5 60.12 (60.02)                                                5.43 (5.51)                                                    5.39 (5.03)    17         ##STR99##                  NHCH.sub.2 COOC.sub.2 H.sub.5                              164-165                                    C.sub.28 H.sub.24 Cl.sub.2 N.sub.2                                    O.sub.6 58.77 (58.79)                                                4.55 (4.71)                                                    5.27 (5.19)    __________________________________________________________________________

                                      TABLE 27    __________________________________________________________________________    Compd.                    m.p          Elemental Analysis (Found)    No. R.sub.1    R.sub.2    (°C.)                                   Formula C   H   N    __________________________________________________________________________    18  --CH.sub.2 CH(C.sub.2 H.sub.5).sub.2                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              142-143                                   C.sub.27 H.sub.32 Cl.sub.2 N.sub.2                                   O.sub.5 60.56                                               6.02                                                   5.23                                           (60.80)                                               (6.06)                                                   (5.24)    19  --CH.sub.2 C(CH.sub.3).sub.3                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              174-175                                   C.sub.28 H.sub.30 Cl.sub.2 N.sub.2                                           59.89.5                                               5.80                                                   5.37                                           (59.97)                                               (5.91)                                                   (5.64)    20  --(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              174-175                                   C.sub.28 H.sub.30 Cl.sub.2 N.sub.2                                           59.89.5                                               5.80                                                   5.37                                           (59.69)                                               (5.64)                                                   (5.34)    21  --CH.sub.2 --CH═C(CH.sub.3).sub.2                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              140-141                                   C.sub.28 H.sub.30 Cl.sub.2 N.sub.2                                           60.12.5                                               5.43                                                   5.39                                           (60.14)                                               (5.41)                                                   (5.31)    22  --CH.sub.2 --C(CH.sub.3)═CH.sub.2                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              123-124                                   C.sub.25 H.sub.26 Cl.sub.2 N.sub.2                                           59.41.5                                               5.19                                                   5.54                                           (59.11)                                               (5.12)                                                   (5.48)    23  CH(C.sub.2 N.sub.5).sub.2                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              128-129                                   C.sub.26 H.sub.30 Cl.sub.2 N.sub.2                                           58.37.5                                               5.93                                                   5.24                                   -3/4H.sub.2 O                                           (58.37)                                               (5.85)                                                   (5.36)    24  --CH.sub.2 --CH═CH.sub.2                   --NHCH.sub.2 COOC.sub.2 H.sub.5                              191-192                                   C.sub.22 H.sub.24 Cl.sub.2 N.sub.2                                           57.61.4                                               5.07                                                   5.60                                   -1/2H.sub.2 O                                           (57.54)                                               (5.16)                                                   (5.58)    25  --CH.sub.2 C(CH.sub.3).sub.3                   --NHCH.sub.2 CH.sub.2 COOC.sub.2 H.sub.6                              172-173                                   C.sub.27 H.sub.32 Cl.sub.2 N.sub.2                                           60.56.5                                               6.02                                                   5.23                                           (60.49                                               6.15                                                   4.99)    __________________________________________________________________________

                                      TABLE 28    __________________________________________________________________________                                      Elemental    compd.              m.p.          Analysis (Found)    No. R.sub.1 R.sub.2 (°C.)                              Formula C   H  N    __________________________________________________________________________    26  CH.sub.2 C(CH.sub.3).sub.3                 ##STR100##                        amorphous solid                              C.sub.26 H.sub.30 Cl.sub.2 N.sub.2 O.sub.6                                      58.10 (57.79                                          5.63 5.62                                             5.21 5.37)    27  CH.sub.2 C(CH.sub.3).sub.3                 ##STR101##                        amorphous solid                              C.sub.26 H.sub.30 Cl.sub.2 N.sub.2 O.sub.6                                      58.10 (57.91                                          5.63 5.62                                             5.21 5.33)    28  CH.sub.2 C(CH.sub.3).sub.3                 ##STR102##                        amorphous solid                              C.sub.28 H.sub.32 Cl.sub.2 N.sub.2 O.sub.7                                      58.03 (58.19                                          5.57 5.64                                             4.83 4.69)    29  CH.sub.2 C(CH.sub.3).sub.3                 ##STR103##                        190-192                              C.sub.28 H.sub.34 Cl.sub.2 N.sub.2 O.sub.6                                      61.20 (61.25                                          6.24 6.28                                             5.10 5.18)    __________________________________________________________________________

Example 34 N-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-ylacetyl!-L-tryptophane

0.2 g of ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl!tryptophaneobtained from the first fraction in Example 32 was dissolved in amixture of 8 ml of methanol and 4 ml of tetrahydrofuran. To the solutionwere added 200 mg of potassium carbonate and 5 ml of water, and themixture was stirred for 3 hours at 60° C. The reaction mixture wasconcentrated under reduced pressure. With 1N hydrochloric acid, the pHof the concentrate was adjusted to 3, followed by extraction with ethylacetate. The organic layer was washed with water and dried, and thesolvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent,methylene chloride:methanol:water=100:15:1) to give 0.13 g of N-trans-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl!-L-tryptophaneas a colorless powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 3700-2200(COOH), 1660(CO), 1485, 1250, 1110, 740

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 2.2-3.2(4H,m), 3.24(3H,s,N--CH₃ ),4.2(1H,m,C₃ --H), 4.63(1H,m), 5.73(1H,s,C₅ --H), 6.34(1H,d,C₆ --H),6.6-7.7(10H,m)

Elemental Analysis for C₂₉ H₂₅ Cl₂ N₃ O₅.1/2C₄ H₈ O₂.1/2H₂ O: Calcd.: C60.10; H 4.88; N 6.78 Found: C 60.11; H 4.89; N 6.69

0.2 g of the compound subsequently eluted in the silica gel columnchromatography was subjected to hydrolysis in substantially the samemanner as described above to give 0.11 g of crystals of a steric isomer,m.p. 165° C.-167° C.

Elemental Analysis for C₂₉ H₂₅ Cl₂ N₃ O₅.1/2C₄ H₈ O₂.1/2H₂ O: Calcd.: C60.53; H 4.84; N 6.83 Found: C 60.44; H 4.88; N 6.83

Example 35

In substantially the same synthetic procedure as in Example 34,compounds shown in Table 29 through Table 33 were obtained.

                                      TABLE 29    __________________________________________________________________________     ##STR104##    compd.                      m.p.              Elemental Analysis (Found)    No. R.sub.1   R.sub.2       (°C.)                                          Formula C   H   N    __________________________________________________________________________         ##STR105##                  NHCH.sub.2 COOH                                130-133   C.sub.28 H.sub.22 Cl.sub.2 N.sub.2                                          O.sub.5. 1/2H.sub.2 O                                                  59.78 (59.81)                                                      4.44 (4.78)                                                          5.36 (4.90)    2         ##STR106##                  NH(CH.sub.2).sub.2 COOH                                195-197   C.sub.27 H.sub.24 Cl.sub.2 N.sub.2                                          O.sub.5 61.49 (61.24)                                                      4.59 (4.35)                                                          5.31 (5.27)    3         ##STR107##                   ##STR108##   158-160  α!.sub.D.sup.25°  =                                -100.3°                                          C.sub.35 H.sub.29 Cl.sub.2 N.sub.3                                          O.sub.5. 1/4H.sub.2 O                                                  64.97 (64.99)                                                      4.60 (4.82)                                                          6.49 (6.14)    4         ##STR109##                  TrpOH         amorphous solid  α!.sub.D.sup.25°                                  = +120.7°                                          C.sub.35 H.sub.28 Cl.sub.2 N.sub.3                                          O.sub.5. 1/4C.sub.4 H.sub.8                                                  65.06 (65.09)                                                      4.70 (5.08)                                                          6.32 (6.00)    5         ##STR110##                  D-TrpOH       157-158  α!.sub.D.sup.25°  =                                +97.0°                                          C.sub.35 H.sub.29 Cl.sub.2 C.sub.3                                          O.sub.5. 3/2H.sub.2 O                                                  62.78 (62.77)                                                      4.81 (4.58)                                                          6.28 (6.04)    __________________________________________________________________________

                                      TABLE 30    __________________________________________________________________________    compd.                    m.p.              Elemental Analysis (Found)    No. R.sub.1   R.sub.2     (°C.)                                        Formula C   H   N    __________________________________________________________________________         ##STR111##                  D-TrpOH     amorphous solid  α!.sub.D.sup.25°                              = -122.9°                                        C.sub.35 H.sub.28 Cl.sub.2 N.sub.3                                        O.sub.5. 3/2H.sub.2 O                                                62.78 (62.51)                                                    4.81 (4.98)                                                        6.28 (6.02)    7         ##STR112##                   ##STR113## 120-125  α!.sub.D.sup.25°  =                              -109.2°                                        C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                        O.sub.5. 1/2H.sub.2 O                                                64.71 (64.91)                                                    4.77 (4.70)                                                        4.57 (4.42)    8         ##STR114##                  PheOH       119-122  α!.sub.D.sup.25°  =                              +142.0°                                        C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                        O.sub.5. 1/2H.sub.2 O                                                64.71 (64.62)                                                    4.77 (4.69)                                                        4.57 (4.41)    9         ##STR115##                  D-PheOH     amorphous solid                                        C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                        O.sub.5. 3/2H.sub.2 O                                                62.86 (62.71)                                                    4.96 (4.66)                                                        4.44 (4.30)    10         ##STR116##                  D-PheOH     amorphous solid                                        C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                        O.sub.5. 3/2H.sub.2 O                                                62.86 (62.89)                                                    4.96 (4.72)                                                        4.44 (4.38)    11         ##STR117##                   ##STR118## 193-194   C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                        O.sub.5 65.68 (65.81)                                                    4.68 (4.91)                                                        4.64 (4.58)    12         ##STR119##                   ##STR120## amorphous solid                                        C.sub.37 H.sub.33 Cl.sub.2 N.sub.3                                        O.sub.5. 2.5H.sub.2 O                                                62.10 (62.32)                                                    5.35 (5.18)                                                        5.87 (5.63)    __________________________________________________________________________

                                      TABLE 31    __________________________________________________________________________    compd.                 m.p.         Elemental Analysis (Found)    No. R.sub.1   R.sub.2  (°C.)                                Formula C   H   N    __________________________________________________________________________    13  C.sub.2 H.sub.5                  NHCH.sub.2 COOH                           167-168                                C.sub.21 H.sub.28 Cl.sub.2 N.sub.2 O.sub.6.                                        54.79                                            4.60                                                6.09                                1/2H.sub.2 O                                        (54.56)                                            (4.57)                                                (6.11)    14  (CH.sub.2).sub.6 CH.sub.3                  NHCH.sub.2 COOH                           185-186                                C.sub.20 H.sub.30 Cl.sub.2 N.sub.2 O.sub.5                                        59.89                                            5.80                                                5.37                                        (59.84)                                            (5.73)                                                (5.53)    15  CH.sub.2 CH(CH.sub.3).sub.2                  NHCH.sub.2 COOH                           233-234                                C.sub.23 H.sub.24 Cl.sub.2 N.sub.2 O.sub.6                                        57.63                                            5.05                                                5.84                                        (57.63)                                            (5.23)                                                (5.66)    16         ##STR121##                  NHCH.sub.2 COOH                           215-216                                C.sub.24 H.sub.24 Cl.sub.2 N.sub.2 O.sub.5                                        58.67 (58.79)                                            4.92 (5.00)                                                5.70 (5.96)    17         ##STR122##                  NHCH.sub.2 COOH                           182-183                                C.sub.24 H.sub.20 Cl.sub.2 N.sub.2 O.sub.6                                        57.27 (57.28)                                            4.01 (4.03)                                                5.57 (5.53)    18  CH.sub.2 CH(C.sub.2 H.sub.6).sub.2                  NHCH.sub.2 COOH                           110-115                                C.sub.26 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                        59.18                                            5.56                                                5.52                                        (58.32)                                            (5.83)                                                (5.47)    19  CH.sub.2 C(CH.sub.3).sub.3                  NHCH.sub.2 COOH                           235-236                                C.sub.24 H.sub.20 Cl.sub.2 N.sub.2 O.sub.5                                        58.43                                            5.31                                                5.68                                        (58.57)                                            (5.58)                                                (5.60)    20  (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                  NHCH.sub.2 COOH                           114-116                                C.sub.24 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5.                                        57.59                                            5.42                                                5.58                                1/2H.sub.2 O                                        (57.24)                                            (5.44)                                                (5.50)    __________________________________________________________________________

                                      TABLE 32    __________________________________________________________________________    Compd.                    m.p          Elemental Analysis (Found)    No. R.sub.1    R.sub.2    (°C.)                                   Formula C   H   N    __________________________________________________________________________    21  --CH.sub.2 --CH═C(CH.sub.3).sub.2                   --NHCH.sub.2 COOH                              146-147                                   C.sub.24 H.sub.24 Cl.sub.2 N.sub.2                                   O.sub.5 58.67                                               4.92                                                   5.70                                           (58.92)                                               (5.05)                                                   (5.77)    22  --CH.sub.2 --C(CH.sub.3)═CH.sub.2                   --NHCH.sub.2 COOH                              200-205                                   C.sub.23 H.sub.22 Cl.sub.2 N.sub.2                                           57.87.5                                               4.65                                                   5.87                                           (57.87)                                               (4.56)                                                   (6.17)    23  --CH(C.sub.2 H.sub.5).sub.2                   --NHCH.sub.2 COOH                              214-215                                   C.sub.24 H.sub.26 Cl.sub.2 N.sub.2                                           58.43.5                                               5.31                                                   5.68                                           (58.56)                                               (5.39)                                                   (5.75)    24  --CH.sub.2 --CH═CH.sub.2                   --NHCH.sub.2 COOH                              128-130                                   C.sub.22 H.sub.20 Cl.sub.2 N.sub.2                                           55.94.5                                               4.48                                                   5.93                                   -1/2H.sub.2 O                                           (56.09)                                               (4.42)                                                   (5.87)    25  --CH.sub.2 C(CH.sub.3).sub.3                   --NHCH.sub.2 CH.sub.2 COOH                              213-214                                   C.sub.25 H.sub.28 Cl.sub.2 N.sub.2                                           59.18.5                                               5.56                                                   5.52                                           (59.12)                                               (5.73)                                                   (5.27)    __________________________________________________________________________

                                      TABLE 33    __________________________________________________________________________    compd.              p.m.          Elemental Analysis (Found)    No. R.sub.1 R.sub.2 (°C.)                              Formula C   H   N    __________________________________________________________________________    26  CH.sub.2 C(CH.sub.3).sub.3                 ##STR123##                        amorphous solid                              C.sub.25 H.sub.24 Cl.sub.2 N.sub.2 O.sub.6                                      57.37 (57.54                                          5.39 5.67                                              5.35 5.22)    27  CH.sub.2 C(CH.sub.3).sub.3                 ##STR124##                        143-146                              C.sub.25 H.sub.28 Cl.sub.2 N.sub.2 O.sub.6                                      57.37 (57.34                                          5.39 5.47                                              5.35 5.34)    28  CH.sub.2 C(CH.sub.3).sub.3                 ##STR125##                        139-141                              C.sub.25 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                              1/2H.sub.2 O                                      58.14 (58.36                                          5.66 5.89                                              5.42 5.55)    29  CH.sub.2 C(CH.sub.3).sub.3                 ##STR126##                        148-150                              C.sub.26 H.sub.28 Cl.sub.2 N.sub.2 O.sub.7                              1/2CH.sub.3 COCH.sub.3                                      56.90 (56.88                                          5.38 5.66                                              4.83 4.77)    __________________________________________________________________________

Example 36Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl!methylamine

In 5 ml of dimethylformamide was dissolved 1.0 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Reference Example 5. To the solution was added 0.3 mlof triethylamine, to which was added dropwise, while stirring underice-cooling, 0.6 g of diphenylphosphoryl azide. The reaction mixture wasstirred for one hour at room temperature, which was then poured intoice-water. The mixture was subjected to extraction with ether. Theorganic layer was washed with water and dried, which was thenconcentrated under reduced pressure. The concentrate was dissolved in100 ml of benzene, which was heated for 30 minutes under reflux. Thereaction mixture was concentrated under reduced pressure. To theconcentrate was added 6 ml of conc. hydrochloric acid, and the mixturewas heated for one hour under reflux. The reaction mixture wasconcentrated under reduced pressure. The concentrate was made alkalineby the addition of a 5% aqueous solution of potassium carbonate,followed by extraction with ethyl acetate. The organic layer was washedwith water and dried, then the solvent was distilled off under reducedpressure. To the residue was added an ethanol solution of 4Nhydrochloric acid to lead it to hydrochloride to give 0.85 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl!methylaminehydrochloride as crystals, m.p. 245°-250° C.

Elemental Analysis for C₂₃ H₂₀ Cl₂ N₂ O₂. HCl.3/2H₂ O: Calcd.: C 56.34;H 4.82; N 5.71 Found: C 56.65; H 4.44; N 6.09

Example 37

By substantially the same procedure as in Example 36, compounds shown inTable 34 were obtained.

                                      TABLE 34    __________________________________________________________________________     ##STR127##    Compd.        m.p.            Elemental Analysis (Found)    No. R         (°C.)                       Formula    C   H   N    __________________________________________________________________________    1   CH.sub.3  114-115                       C.sub.17 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2                                  58.13                                      4.59                                          7.98                                  (58.16)                                      (4.79)                                          (7.93)         ##STR128##                  250-253                       C.sub.23 H.sub.26 Cl.sub.2 N.sub.2 O.sub.2.HCl.                       1/4H.sub.2 O                                  58.23 (58.08)                                      5.52 (5.66)                                          5.91 (5.68)    3   CH(CH.sub.3).sub.2                  136-137                       C.sub.19 H.sub.20 Cl.sub.2 N.sub.2 O.sub.2                                  60.17                                      5.31                                          7.39                                  (59.93)                                      (5.38)                                          (7.06)    __________________________________________________________________________

Example 38 Ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl-methylaminocarbonyl!glycine

In 4 ml of dimethylformamide was dissolved 0.3 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Reference Example 5. To the solution was added 0.15 mlof triethylamine. To the mixture was added, while stirring underice-cooling, 0.18 g of diphenylphosphoryl azide. The reaction mixturewas stirred for one hour at room temperature, to which was addedice-water, followed by extraction with ethyl acetate. The organic layerwas washed with water, dried and concentrated under reduced pressure. Tothe concentrate was added 10 ml of benzene, and the mixture was heatedfor one hour under reflux while stirring. To the reaction mixture wereadded 0.14 g of glycine ethyl ester hydrochloric acid and 0.15 ml oftriethylamine. The mixture was then heated for 3 hours under reflux. Thereaction mixture was concentrated under reduced pressure. Theconcentrate was subjected to extraction with ethyl acetate. The organiclayer was washed with water and dried, then the solvent was distilledoff under reduced pressure. Crystals obtained from the residue wererecrystallized from a mixture of ethyl acetate and hexane to give 0.33 gof the title compound as white crystals, m.p. 200°-201° C.

Elemental Analysis for C₂₈ H₂₇ Cl₂ N₃ O₅ : Calcd.: C 60.44; H 4.89; N7.55 Found: C 60.29; H 4.82; N 7.68

Example 39

In 8 ml of methanol was dissolved 0.2 g of ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl-methylaminocarbonyl!glycine.To the solution were added 0.2 g of potassium carbonate and 2 ml ofwater, and the mixture was stirred for 3 hours at 60° C. The reactionmixture was concentrated under acidified to pressure, to which was addedwater, followed by extraction with ether. The aqueous layer wasacidified to pH 3 with dilute hydrochloric acid, which was subjected toextraction with ethyl acetate. The organic layer was washed with waterand dried, then the solvent was distilled off under reduced pressure toleave crystalline residue. Recrystallization from ethyl acetate afforded0.18 g of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl-methylaminocarbonyl!glycineas colorless needles, m.p. 153°-155° C.

Elemental Analysis for C₂₆ H₂₃ Cl₂ N₃ O₅.1/4H₂ O: Calcd.: C 58.60; H4.45; N 7.88 Found: C 58.63; H 4.42; N 7.58

Example 40 Ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycine

In 10 ml of acetonitrile was dissolved 0.4 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylamineobtained in Example 36. To the solution were added 0.15 g of ethylchloroacetate and 0.5 g of potassium carbonate. The mixture was heatedunder reflux for 15 hours while stirring. The reaction mixture wasconcentrated under reduced pressure, and the concentrate was subjectedto extraction with ethyl acetate. The organic layer was washed withwater and dried, then the solvent was distilled under reduced pressure.The residue was purified by means of a silica gel column chromatography(eluent, hexane ethyl acetate=3:2 to 1:2) to give 0.28 g of ethyl esterof N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycineas an oily product. This product was made into hydrochloride salt togive white crystals, m.p. 182°-184° C.

Elemental Analysis for C₂₇ H₂₆ Cl₂ N₂ O₄.HCl: Calcd.: C 58.98; H 4.95; N5.09 Found: C 58.70; H 4.98; N 5.07

Example 41 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycine

In 6 ml of methanol was dissolved 0.15 g of ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycineobtained in Example 40. To the solution were added 0.4 g of potassiumcarbonate and 2 ml of water. The mixture was stirred for 2 hours at 50°C. The reaction mixture was concentrated under reduced pressure, whosepH was adjusted to 3 with dilute hydrochloric acid, followed byextraction with methylene chloride. The organic layer was washed withwater and dried, then the solvent was distilled off under reducedpressure. From the residue was obtained 0.13 g of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycineas crystals, m.p. 224°-226° C.

Elemental Analysis for C₂₅ H₂₂ Cl₂ N₂ O₄.1/2H₂ O: Calcd.: C 60.74; H4.69; N 5.67 Found: C 60.74; H 4.48; N 5.70

Example 42 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!-N-methylglycine

To 0.13 g of ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycineobtained in Example 40 were added 2 ml of formalin and 2 ml of oxalicacid; The mixture was heated at 80° C. for 2 hours. The reaction mixturewas concentrated under reduced pressure, and the concentrate wassubjected to extraction with ethyl acetate. The organic layer was washedwith an aqueous solution of sodium hydrogencarbonate, then with water,followed by drying. The solvent was distilled off under reducedpressure. The residue was dissolved in 6 ml of methanol. To the solutionwere added 0.2 g of potassium carbonate and 2 ml of water. The mixturewas stirred for 2 hours at 60° C. The reaction mixture was concentratedunder reduced pressure, to which was added water, followed by extractionwith ether. The aqueous layer was acidified to pH 4 with dilutehydrochloric acid, followed by extraction with methylene chloride. Theorganic layer was washed with water and dried, then the solvent wasdistilled off under reduced pressure. From the residue was obtained 0.1g of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!-N-methylglycineas crystals, m.p. 195°-197° C.

Elemental Analysis for C₂₆ H₂₄ Cl₂ N₂ O₄.1/4H₂ O: Calcd.: C 61.97; H4.90; N 5.56 Found: C 61.90; H 4.73; N 5.67

Example 43 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!-N-acetylglycine

In 4 ml of methanol was dissolved 60 mg of ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycineobtained in Example 40. To the solution were added 0.2 ml of aceticanhydride and 0.2 ml of triethylamine. The mixture was heated for onehour under reflux while stirring. The reaction mixture was concentratedunder reduced pressure, which was subjected to extraction with ethylacetate. The organic layer was washed with an aqueous solution ofpotassium hydrogensulfate, an aqueous solution of sodiumhydrogencarbonate and water, which was then dried, followed bydistilling off the solvent. The residue was dissolved in 4 ml ofmethanol, to which was added 2 ml of a 5% aqueous solution of potassiumcarbonate. The mixture was stirred for 30 minutes at 60° C. The reactionmixture was concentrated under reduced pressure, to which was added 1Nhydrochloric acid to acidify the solution, followed by extraction withethyl acetate. The organic layer was washed with water and dried, thenthe solvent was distilled off under reduced pressure. From the residue,45 mg of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!-N-acetylglycine was obtained as crystals, m.p. 143°-145° C.

Elemental Analysis for C₂₇ H₂₄ Cl₂ N₂ O₅.1/4H₂ O: Calcd.: C 60.96; H4.64; N 5.27 Found: C 60.90; H 4.39; N 5.32

Example 44 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!-N-benzoylglycine

In 10 ml of methylene chloride was dissolved 0.15 g of ethyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycineobtained in Example 40. To the solution were added 90 mg of benzoicanhydride, 0.1 ml of triethylamine and 10 mg of 4-dimethylaminopyridine.The mixture was stirred for 15 hours at room temperature. The reactionmixture was concentrated under reduced pressure, and the residue wassubjected to extraction with ethyl acetate. The organic layer was washedwith water and dried, then the solvent was distilled off under reducedpressure. The residue was purified by means of a silica gel columnchromatography (eluent, hexane:ethyl acetate=3:2) to give an oilyproduct. The oily product was dissolved in a mixture of 5 ml of methanoland 2 ml of tetrahydrofuran. To the solution were added 0.2 g ofpotassium carbonate and 2 ml of water. The mixture was then stirred for2 hours at 60° C. The reaction mixture was concentrated under reducedpressure. To the concentrate was added dilute hydrochloric acid toadjust the pH to 2, followed by extraction with ethyl acetate. Theorganic layer was washed with water and dried, then the solvent wasdistilled off under reduced pressure. From the residue was obtained 75mg of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!-N-benzoylglycineas amorphous solid matter.

IRν_(max) ^(KBr) cm⁻¹ : 3700-2200(COOH), 1740(CO), 1670(CO), 1420, 1250,1170, 1080, 750

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 3.8-5.1(6H,m), 5.75(1H,s,C₅ --H),6.40(1H,s,C₆ --H), 7.0-7.8(16H,m)

Elemental Analysis for C₃₂ H₂₆ Cl₂ N₂ O₅.2/3H₂ O: Calcd.: C 62.34; H4.74; N 4.54 Found: C 62.40; H 4.44; N 4.32

Example 45Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-(3-methoxycarbonylmethylcarbamoyl)methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

To a mixture of 0.25 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl!methylamineobtained in Example 36, 0.1 g of malonic acid half ester potassium saltand 4 ml of dimethylformamide were added, while stirring underice-cooling, 0.13 g of diethyl phosphorocyanidate and 0.23 ml oftriethylamine. The reaction mixture was stirred for 40 minutes at roomtemperature, to which was added ice-water, followed by extraction withethyl acetate. The organic layer was washed with an aqueous solution ofsodium hydrogensulfate, an aqueous solution of sodium hydrogen carbonateand water, successively, which was then dried. The solvent was distilledoff, and the residue was purified by means of a silica gel columnchromatography (eluent, hexane:ethyl acetate: ethanol=10:10:1) to give0.22 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-(3-methoxycarbonylmethylcarbamoyl)methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepineas a white powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 3370(NH), 2950, 1745(CO), 1670(CO), 1480, 1420,1250

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 3.31(2H,s,COCH₂ CO₂),3.74(3H,s,OCH₃), 3.7-4.2(3H,m), 4.8(1H,d), 5.6(1H,d), 5.8(1H,s,C₅ --H),6.42(1H,d,C₆ --H), 7.2-7.8(1H,m)

Elemental Analysis for C₂₇ H₂₄ Cl₂ N₂ O₅.1/2H₂ O: Calcd.: C 60.46; H4.70; N 5.22 Found: C 60.27; H 4.85; N 4.95

In 5 ml of methanol was dissolved 0.15 g of the white powdery productobtained above. To the solution were added 0.2 g of potassium carbonateand 1.5 ml of water, then the mixture was stirred for 2 hours at 50° C.The reaction mixture concentrated under reduced pressure. Theconcentrate was neutralized with dilute hydrochloric acid, followed byextraction with ethyl acetate. The organic layer was washed with waterand dried, then the solvent was distilled off under reduced pressure.From the residue was obtained 0.14 g ofTrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-(3-hydroxycarbonylmethylcarbamoyl)methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepineas a white powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 3700-2200(COOH), 1730(CO), 1670(CO), 1480, 1240

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 3.31(2H,s,--CO CH₂ COOH),3.7-4.2(3H,m), 4.75(1H,d), 5.62(1H,d), 5.77(1H,s,C₅ --H), 6.44(1H,d,C₆--H), 7.04(1H,t,NH), 7.2-7.7(11H,m)

Elemental Analysis for C₂₆ H₂₂ Cl₂ N₂ O₅.1/2H₂ O: Calcd.: C 59.78; H4.44; N 5.36 Found: C 59.47; H 4.69; N 5.13

Example 46 Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,23,5-tetrahydro-4,1-benzoxazepine-3-methanol and3,5-trans-7-chloro-3-chloromethyl-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

In mixture of 12 ml of glacial acetic acid and 10 ml of water wassuspended 2.0 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl!methylaminehydrochloride obtained in Example 36. To the suspension was addeddropwise, while stirring under ice-cooling, 1 ml of an aqueous solutionof 1.0 g of sodium nitrite, in the course of 10 minutes. The reactionmixture was stirred for one hour at room temperature, which was added toice-water, followed by extraction with ethyl acetate. The organic layerwas washed with an aqueous solution of sodium hydrogencarbonate andwater, successively, which was then dried, followed by distilling offthe solvent under reduced pressure. The residue was dissolved in 50 mlof methanol, to which was added 5 ml of a 10% aqueous solution ofpotassium carbonate. The mixture was stirred for 15 minutes at 60° C.The reaction mixture was concentrated under reduced pressure. Theconcentrate was subjected to extraction with ethyl acetate. The organiclayer was washed with water and dried, then the solvent was distilledoff under reduced pressure. The residue was purified by means of asilica gel column chromatography (eluent, hexane:ethyl acetate=4:1 to1:1). From the preceding portion of the eluate, 0.2 g oftrans-7-chloro-3-chloromethyl-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepineas colorless prisms, m.p. 177°-179° C.

Mass spectrum (m/e): 445 (M⁺)

Elemental Analysis for C₂₃ H₁₈ Cl₃ NO₂ : Calcd.: C 61.83; H 4.06; N 3.14Found: C 62.11; H 4.01; N 3.38

From the subsequent portion of the eluate, 1.05 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methanolas colorless needles, m.p. 158°-159° C.

Mass spectrum (m/e): 427, 429 (M⁺)

Elemental Analysis for C₂₃ H₁₉ Cl₂ NO₃ : Calcd.: C 64.49; H 4.47; N 3.27Found: C 64.36; H 4.39; N 3.34

Example 47

By substantially the same procedure as in Example 46, compounds shown inTable 35 were obtained.

                                      TABLE 35    __________________________________________________________________________     ##STR129##    compd.        m.p.        Elemental Analysis (Found)    No. R         (°C.)                       Formula                              C   H   N    __________________________________________________________________________    1   CH.sub.3  208-209                       C.sub.17 H.sub.15 Cl.sub.2 NO.sub.3                              57.97                                  4.29                                      3.98                              (58.18)                                  (4.46)                                      (3.79)         ##STR130##                  171-172                       C.sub.23 H.sub.25 Cl.sub.2 NO.sub.3                              63.60 (63.60)                                  5.80 (5.89)                                      3.22 (3.02)    3   CH(CH.sub.3).sub.2                  154-155                       C.sub.19 H.sub.19 Cl.sub.2 NO.sub.3                              60.01                                  5.04                                      3.68                              (59.83)                                  (4.91)                                      (3.79)    __________________________________________________________________________

Example 48Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-carboxylicacid

In 20 ml of acetone was dissolved 0.5 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methanolobtained in Example 46. To the solution was added dropwise, whilestirring at room temperature, 0.5 ml of a Jones' reagent. The reactionmixture was stirred for one hour at room temperature, which was thenconcentrated under reduced pressure The concentrate was subjected toextraction with ethyl acetate. The organic layer was washed with waterand dried, then the solvent was distilled off under reduced pressure.From the residue was obtained 0.23 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,213,5-tetrahydro-4,1-benzoxazepine-3-carboxylicacid as white crystals, m.p.177°-178° C.

Elemental Analysis for C₂₃ H₁₇ Cl₂ NO₄ : Calcd.: C 62.46; H 3.87; N 3.17Found: C 62.24; H 3.93; N 3.30

Example 49

By substantially the same synthetic procedure as in Example 48,compounds listed in Table 36 were obtained.

                                      TABLE 36    __________________________________________________________________________     ##STR131##    compd.        m.p.                Elemental Analysis (Found)    No. R         (°C.)                       Formula        C   H   N    __________________________________________________________________________    1   CH.sub.3  167-168                       C.sub.17 H.sub.13 Cl.sub.2 NO.sub.4.1/4C.sub.4                       H.sub.10 O.1/4H.sub.2 O                                      55.54                                          4.14                                              3.60                                      (55.72)                                          (4.34)                                              (3.34)         ##STR132##                  189-190                       C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                                      57.88 (57.76)                                          4.35 (4.55)                                              3.55 (3.43)    3   CH(CH.sub.3).sub.2                  181-182                       C.sub.19 H.sub.17 Cl.sub.2 NO.sub.4                                      61.62                                          5.17                                              3.12                                      (61.69)                                          (5.39)                                              (3.39)    __________________________________________________________________________

Example 50 Ethyl ester of 3-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!thioglycolicacid

In 6 ml of acetonitrile was dissolved 0.2 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-chloromethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine.To the solution were added 0.08 g of ethyl thioglycolate and 0.1 g ofcesium fluoride. The mixture was heated under reflux for 40 minuteswhile stirring. The reaction mixture was concentrated under reducedpressure. The concentrate was subjected to extraction with ethylacetate. The organic layer was washed with water and dried, then thesolvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent,hexane:ethyl acetate 4:1) to afford 0.16 g of ethyl 3-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!thioglycolateas colorless needles, m.p.153°-154° C.

Elemental Analysis for C₂₇ H₂₅ Cl₂ NO₄ S: Calcd.: C 61.13; H 4.75; N2.64 Found: C 61.04; H 4.72; N 2.54

Example 51 3-Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycolicacid

In a mixture of 4 ml of methanol and 2 ml of tetrahydrofuran wasdissolved 0.11 g of 3-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!thioglycolicacid ester. To the solution were added 0.2 g of potassium carbonate and2 ml of water, then the mixture was stirred for one hour at 60° C. Thereaction mixture was concentrated under reduced pressure. Theconcentrate was rendered acid with dilute hydrochloric acid, which wasthen subjected to extraction with ethyl acetate. The organic layer waswashed with water and dried, then the solvent was distilled off underreduced pressure. From the residue was obtained 90 mg of 3-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!thioglycolicacid as white crystals, m.p.148°-149° C.

Elemental Analysis for C₂₅ H₂₁ Cl₂ NO₄ S: Calcd.: C 59.77; H 4.21; N2.79 Found: C 59.89; H 4.31; N 2.77

Example 52 3-Trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycolicacid

To a suspension of 50 mg of sodium hydride in 4 ml of dimethylformamidewas added 0.2 g oftrans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine3-methanol,while stirring under ice-cooling. The mixture was stirred for 10 minutesat the same temperature, to which was then added 0.1 g of ethylchloroacetate, followed by stirring for 30 minutes at room temperature.The reaction mixture was poured into ice-water, which was subjected toextraction with ethyl acetate. The organic layer was washed with anaqueous solution of potassium hydrogensulfate, an aqueous solution ofsodium hydrogencarbonate and water, successively and dried, then thesolvent was distilled off under reduced pressure. The residue waspurified by means of a silica gel column chromatography (eluent, hexaneethyl acetate=5:1) to give crystals. The crystals were dissolved in 5 mlof methanol. To the solution were added 0.2 g of potassium carbonate and2 ml of water. The mixture was stirred for 5 hours at 60° C. Thereaction mixture was concentrated under reduced pressure. Theconcentrate was rendered acid with dilute hydrochloric acid, followed byextraction with ethyl acetate. The organic layer was washed with waterand dried, then the solvent was distilled off under reduced pressure.From the residue was obtained 50 mg of 3-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl!glycolicacid as white crystals, m.p.92°-94° C.

Elemental Analysis for C₂₅ H₂₁ Cl₂ NO₅.1/2C₄ H₁₀ O.1/2H₂ O: Calcd.: C60.91; H 5.11; N 2.63 Found: C 60.95; H 4.99; N 2.77

Example 53 Methyl ester of N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylcarbonyl!tryptophane

By substantially the same procedure as in Example 32, 0.4 g of3,5-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-carboxylicacid obtained in. Example 48 was subjected to the reaction to give acrude product, which was purified by means of a silica gel columnchromatography (eluent, hexane:ethyl acetate: methylene chloride=9:3:1).From the preceding portion of the eluate, 0.25 g of the product wasobtained as a white powdery product.

IRν_(max) ^(KBr) cm⁻¹ : 3400(NH), 1740(CO), 1690(CO), 1655(CO)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 3.44(2H,d), 3.64(3H,s,OCH₃),4.55(1H,s,C₃ --H), 4.70(1H,d,PhCH₂), 5.03(1H,m), 5.69(1H,d,PhCH₂),5.79(1H,s,C₅ --H), 6.37(1H,d,C₆ --H), 6.9-8.2(15H,m)

From the subsequent portion of the eluate, 0.22 g of the title compoundas an amorphous solid product.

IRν_(max) ^(KBr) cm⁻¹ : 3400(NH), 1740(CO), 1695(CO), 1660(CO), 1520,1480, 1240

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 3.2-3.55(2H,m), 3;70(3H,s,OCH₃),4.53(1H,s,C₃ --H), 4.62(1H,d), 5.06(1H,m), 5.63(1H,d), 5.76(1H,s,C₅--H), 6.33(1H,d,C₆ --H), 6.8-8.4(15H,m)

Example 54 N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylcarbonyl!tryptophane

N-trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylcarbonyl!tryptophaneethyl ester obtained in Example 53 was subjected to substantially thesame procedure as in Example 34. From 0.25 g of the compound obtained asthe preceding eluate, 70 mg of a colorless crystalline product wasobtained, m.p.250°-155° C. (decomp.).

Elemental Analysis for C₃₄ H₂₇ Cl₂ N₃ O₅.H₂ O: Calcd.: C 63.16;. H 4.52;N 6.50 Found: C 63.34; H 4.63; N 6.42

From 0.22 g of the compound eluted subsequently, 0.11 g of a colorlessamorphous solid product was obtained

IRν_(max) ^(KBr) cm⁻¹ : 3700-2200(NH,COOH), 1740(CO), 1680(CO),1660(CO), 1525, 1240

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 3.40(2H,m), 4.54(1H,s), 4.63(1H,d),5.05(1H,m), 5.63(1H,d), 5.70(1H,s,C₅ --H), 6.31(1H,d,C₆ --H),6.8-8.4(15H,m)

Elemental Analysis for C₃₄ H₂₇ Cl₂ N₃ O₅ : Calcd.: C 64.97; H, 4.33; N6.67 Found: C 64.70; H, 4.58; N 6.49

Example 55N-(cis-7-chloro-1-isopropyl-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetyl)glycineethyl ester

In 5 ml of methanol was dissolved 0.3 g of ethyl ester of3,5-cis-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid ethyl ester disclosed in JPA S57(1982)-35576. To the solution wereadded 0.3 g of potassium carbonate and 2 ml of water. The mixture wasstirred for 8 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure. To the concentrate was added water,which was subjected to extraction with ether. The aqueous layer wasseparated, to which was added dilute hydrochloric acid to adjust its pHto 3. The organic layer was washed with water and dried, then thesolvent was distilled off under reduced pressure. From the residue wasobtained 0.15 g of a powdery product. The product and 0.07 g of glycineethyl ester hydrochloride were dissolved in 4 ml of dimethylformamide.To the solution were added, while stirring under ice-cooling, 0.1 g ofdiethyl phosphorocyanidate and, then, 0.2 ml of triethylamine. Thereaction mixture was stirred for one hour at room temperature, which waspoured into ice-water, followed by extraction with ethyl acetate. Theorganic layer was washed with an aqueous solution of potassiumhydrogensulfate, an aqueous solution of hydrogencarbonate and water,successively, which was then dried. The solvent was distilled off underreduced pressure. The residue was purified by means of a silica gelcolumn chromatography (eluent, hexane:ethyl acetate=2:1 to 3:2) toafford 0.11 g of N-cis-7-chloro-1-isopropyl-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetyl!glycineethyl ester as a crystalline product, m.p.188° C.-190° C.

Elemental Analysis for C₂₄ H₂₇ ClN₂ O₅ : Calcd.: C 62.81; H 5.93; N 6.10Found: C 62.52; H 6.10; N 6.04

Example 56 N-cis-7-chloro-1-isopropyl-5-phenyl)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl!glycine

In a mixture of 2 ml of methanol and 1 ml of water was suspended 48 mgofN-(trans-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl)glycineethyl ester obtained in Example 55. To the suspension was added 0.1 g ofpotassium carbonate. The mixture was stirred for 6 hours at roomtemperature. The reaction mixture was adjusted to pH 4 with dilutehydrochloric acid, which was subjected to extraction with ethyl acetate.The organic layer was washed with water and dried, then the solvent wasdistilled off under reduced pressure. Crystals obtained form the residuewere recrystallized from ether and hexane to afford 29 mg ofN-(cis-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl)glycineas white needles.

IRν_(max) ^(KBr) cm⁻¹ : 3700-2200(COOH), 1710(CO), 1680(CO), 1480, 1250,700

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 2.7-3.4(2H,m), 4.4(1H,dd,C₃ --H),4.75(1H,d), 5.34(1H,s,C₅ --H), 5.5(1H,d), 6.48(1H,s,C₆ --H),6.9-7.6(12H,m)

Elemental Analysis for C₂₄ H₂₀ ClNO₄.3/4H₂ O: Calcd.: C 66.20; H 4.98; N3.22 Found: C 66.12; H 5.19; N 2.97

Example 57Trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-butyricacid ethyl ester

(1) A solution of oxalyl chloride (0.72 ml) in methylene chloride (10ml) was cooled to -65° C., to which was added dropwise a solution ofdimethyl sulfoxide (0.63 ml) in methylene chloride (2 ml) taking 5minutes, followed by stirring for 5 minutes. To the mixture was addeddropwise, taking 15 minutes, a solution oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol(2.5 g) obtained in Example 47 in methylene chloride (15 ml), which wasstirred for 10 minutes. To the resultant mixture was added triethylamine(3.45 ml) taking 5 minutes, then the cooling bath was removed. Themixture was stirred for 10 minutes at room temperature, to which wasthen added 1N hydrochloric acid (50 ml), followed by stirring. Themethylene chloride layer was dried over anhydrous magnesium sulfate,then the solvent was distilled off under reduced pressure to leavetrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde(2.3 g) as an oily product.

IRν_(max) ^(Neat) cm⁻¹ : 1720, 1670(C═O)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 1.29(3H,t,J=7.1 Hz),1.29(3H,d,J=7.0 Hz), 1.56(3H,d,J=6.8 Hz), 2.7-2.85(2H,m),3.91(1H,t,J=6.5 Hz), 4.19(2H,q,J=7.1 Hz), 4.75-5.0(1H,m),5.90(1H,dt,J=15.6, 1.5 Hz), 6.01H,s), 6.51(1H,d,J=2.4 Hz),6.97(1H,dt,J=15.6, 7.2 Hz), 7.2-7.8(6H,m), 9.83(1H,s)

(2) In toluene (20 ml) was dissolvedtrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde(1.5 g). To the solution was added(ethoxycarbonylmethylene)-triphenylphosphorane (2.0 g), and the mixturewas stirred for 3 hours at 90° C. The solvent was distilled off, and theresidue was purified by means of a silica gel column chromatography(hexane:ethyl acetate=10:1) to give ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-crotonicacid (1.28 g) as prisms, m.p.126°-127° C.

IRν_(max) ^(KBr) cm⁻¹ : 1715(C═O), 1670(C═C)

Elemental Analysis for C₂₄ H₂₅ Cl₂ NO₄ : Calcd.: C 62.34; H 5.45; N 3.03Found: C 62.47; H 5.28; N 3.08

(3) In ethyl acetate (20 ml) was dissolved ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-crotonicacid (0:45 g). To the solution was added 10% palladium carbon (0.1 g),and the mixture was subjected to catalytic reduction at roomtemperatures under atmospheric pressure. The theoretical amount ofhydrogen was allowed to be absorbed, then the catalyst was removed,followed by distilling off ethyl acetate under reduced pressure. Theresidue was crystallized from a small volume of hexane to give ethylester oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-butyricacid (0.37 g) as prisms, m.p.100°-101° C.

IRν_(max) ^(KBr) cm⁻¹ : 1730, 1670(C═O)

Elemental Analysis for C₂₄ H₂₇ Cl₂ NO₄ : Calcd.: C 62.07; H 5.86; N 3.02Found: C 62.35; H 5.93; N 2.95

Example 58Trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-butyricacid

In ethanol (5 ml) was dissolved ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-butyricacid (0.25 g). To the solution was added 1N sodium hydroxide (4 ml),then the mixture was stirred for 30 minutes at room temperatures. Themixture was acidified with 1N aqueous solution of hydrochloric acid (50ml), followed by extraction with ethyl acetate (100 ml). The ethylacetate layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to leavetrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-butyricacid (0.20 g) as prisms, m.p.158°-160° C.

IRν_(max) ^(KBr) cm⁻¹ : 1710, 1670(C═O)

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₄ : Calcd.: C 60.56; H 5.31; N 3.21Found: C 60.62; H 5.18; N 3.23

Example 59 Ethyl ester of N-trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

Trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.4 g) obtained in Example 5 and glycine ethyl ester hydrochloridewere subjected to substantially the same procedure as in Example 24 togive ethyl ester of N-trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.47 g) as needles, m.p. 137°-138° C.

IRν_(max) ^(KBr) cm⁻¹ : 3360(NH), 1745, 1655(C═O)

Elemental Analysis for C₂₆ H₃₂ N₂ O₅ : Calcd.: C 69.01; H 7.13; N 6.19Found: C 69.01; H 7.18; N 6.26

Example 60 N-trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

Ethyl ester of N-trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.3 g) obtained in Example 59 was subjected to hydrolysis insubstantially the same manner as in Example 35 to afford N-trans-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.26 g) as prisms, m.p.220°-223° C.

IRν_(max) ^(KBr) cm⁻¹ : 1755, 1670, 1630(C═O)

Elemental Analysis for C₂₄ H₂₆ N₂ O₅ : Calcd.: C 67.91; H 6.65; N 6.60Found: C 67.96; H 6.86; N 6.69

Example 61 Ethyl ester of N-trans-5-(2-fluorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

Trans-5-(2-fluorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.4 g) obtained in Example 6 was allowed to react with glycineethyl ester hydrochloride in substantially the same manner as in Example24 to afford ethyl ester of N-trans-5-(2-fluorophenyl)-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.45 g) as needles, m.p.166°-168° C.

IRν_(max) ^(KBr) cm⁻¹ : 3370(NH), 1750, 1660(C═O)

Elemental Analysis for C₂₅ H₂₉ FN₂ O₅ : Calcd.: C 65.78; H 6.40; N 6.14Found: C 65.89; H 6.34; N 6.15

Example 62 N-trans-5-(2-fluorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

Ethyl ester of N-trans-5-(2-fluorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.3 g) obtained in Example 61 was subjected to hydrolysis insubstantially the same manner as in Example 25 to afford N-trans-5-(2-fluorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.27 g) as prisms, m.p.201°-203° C.

IRν_(max) ^(KBr) cm⁻¹ : 1755, 1670, 1630(C═O)

Elemental Analysis for C₂₃ H₂₅ FN₂ O₅ : Calcd.: C 64.48; H 5.88; N 6.54Found: C 64.54; H 5.95; N 6.51

Example 63 Ethyl ester of N-trans-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetic acid

In N,N-dimethylformamide (10 ml) were dissolvedtrans-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.4 g) obtained in Example 6 and glycine ethyl ester hydrochloride(0.18 g). To the solution were added, under ice-cooling, diethylphosphorocyanidate (0.22 g) and triethylamine (0.35 ml). The mixture wasstirred for 30 minutes at room temperature, to which were then addedwater (100 ml) and ethyl acetate (100 ml), followed by extraction. Theethyl acetate layer was washed with 1N hydrochloric acid and an aqueoussolution of sodium hydrogencarbonate, which was then dried on anhydrousmagnesium sulfate, followed by distilling off the solvent under reducedpressure. The residue was purified by means of a silica gel columnchromatography (hexane:ethyl acetate=1:1) to give ethyl ester of N-trans-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetic acid (0.45 g) as needles, m.p.135°-137° C.

IRν_(max) ^(KBr) cm⁻¹ : 1750, 1670(C═O)

Elemental Analysis for C₂₆ H₃₂ N₂ O₆ : Calcd.: C 66.65; H 6.88; N 5.98Found: C 66.72; H 6.91; N 5.98

Example 64 N-trans-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

In ethanol (5 ml) was dissolved ethyl ester of N-trans-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.3 g) obtained in Example 63. To the solution was added 1N sodiumhydroxide, and the mixture was stirred for 15 minutes, which wasacidified by the addition of 1N aqueous solution of hydrochloric acid(50 ml), followed by extraction with ethyl acetate (100 ml). The ethylacetate layer was washed with water, which was then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto leave N-trans-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.27 g) as prisms, m.p.210°-211° C.

IRν_(max) ^(KBr) cm⁻¹ : 1760, 1670, 1630(C═O)

Elemental Analysis for C₂₄ H₂₈ N₂ O₆ : Calcd.: C 65.44; H 6.41; N 6.36Found: C 65.32; H 6.38; N 6.33

Example 65Trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol

In tetrahydrofuran (7 ml) were dissolvedtrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.5 g) obtained in Reference Example 5, and N-methylmorpholine(0.15 ml). To the solution was added ethyl chlorocarbonate (0.13 ml) at-10° C., and the mixture was stirred for 10 minutes. To the mixture wasadded sodium borohydride (0.15 g), to which was then added dropwisemethanol taking 5 minutes, followed by stirring for 30 minutes at 0° C.The reaction mixture was poured into 1N hydrochloric acid (50 ml),followed by extraction with ethyl acetate (100 ml). The ethyl acetatelayer was washed with an aqueous solution of sodium hydrogencarbonate,then dried over anhydrous magnesium sulfate, followed by distilling offthe solvent under reduced pressure. The residue was purified by means ofa silica gel column chromatography to affordtrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol(0.41 g) as prisms, m.p.188°-189° C.

IRν_(max) ^(KBr) cm⁻¹ : 3430(OH), 1650(C═O)

Elemental Analysis for C₂₀ H₂₁ Cl₂ NO₃ : Calcd.: C 60.92; H 5.37; N 3.55Found: C 61.12; H 5.39; N 3.72

Example 66 Ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-41,-benzoxazepine-3-acetyl!aminoaceticacid

In N,N-dimethylformamide (10 ml) were dissolvedtrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid-(0.3 g) and glycine ethyl ester hydrochloride (0.12 g). To thesolution were added, under ice-cooling, diethyl phosphorocyanidate (0.15g) and triethylamine (0.24 ml). The mixture was stirred for 30 minutesat room temperature, to which were added water (100 ml) and ethylacetate (100 ml), followed by extraction. The ethyl acetate layer waswashed with 1N hydrochloric acid and an aqueous solution of sodiumhydrogencarbonate, which was then dried over anhydrous magnesiumsulfate, followed by distilling off the solvent under reduced pressure.The residue was purified by means of a silica gel column chromatography(hexane:ethyl acetate=1:1) to afford ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.31 g) as needles, m.p.197°-199° C.

IRν_(max) ^(KBr) cm⁻¹ : 1755, 1670, 1655(C═O)

Elemental Analysis for C₂₄ H₂₆ Cl₂ N₂ O₅ : Calcd.: C 58.43; H 5.31; N5.68 Found: C 58.73; H 5.33; N 5.80

Example 67 N-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

In ethanol (10 ml) was dissolved ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.2 g) obtained in Example 66. To the solution was added 1N sodiumhydroxide (2 ml), and the mixture was stirred for 15 minutes. To thereaction mixture was added 1N aqueous solution of hydrochloric acid (100ml) to make the solution acid, followed by extraction with ethyl acetate(100 ml). The ethyl acetate layer was washed with water, which was thendried over anhydrous magnesium sulfate, followed by distilling off thesolvent to leave N-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid (0.18 g) as crystals, m.p.134°-135° C.

IRν_(max) ^(KBr) cm⁻¹ : 1725, 1650(C═O)

Elemental Analysis for C₂₂ H₂₂ Cl₂ N₂ O₅.1/2Et₂ O: Calcd.: C 57.38; H5.42; N 5.58 Found: C 57.48; H 5.59; N 5.58

Example 68

By substantially the same synthetic method as in Example 66, compoundslisted in Table 37 and Table 38 were obtained as crystalline or oilyproducts.

                                      TABLE 37    __________________________________________________________________________     ##STR133##    compd.          m.p.         Elemental Analysis (Found)    No. R           (°C.)                         Formula C   H   N    __________________________________________________________________________    1   NHCH.sub.2 CH.sub.2 COOEt                    182-183                         C.sub.26 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                 59.18                                     5.56                                         5.52                                 (59.13)                                     (5.56)                                         (5.45)         ##STR134## 160-164                         C.sub.28 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                 62.71 (62.55)                                     5.08 (5.11)                                         5.04 (4.86)    3         ##STR135## 187-188                         C.sub.31 H.sub.32 Cl.sub.2 N.sub.2 O.sub.5                                 63.81 (63.97)                                     5.53 (5.59)                                         4.80 (4.98)    __________________________________________________________________________

                                      TABLE 38    __________________________________________________________________________    compd.    No. R           IRν.sub.max.sup.neat cm.sup.-1                             .sup.1 H-NMR spectrum (200 MHZ,    __________________________________________________________________________                             CDCl.sub.3)         ##STR136## 1745, 1660 (CO)                             1.29(3H, d, J=7.0Hz), 1.54, 1.56(3H, both d,                             J=6.6Hz), 2.6-3.05(2H, m), 3.76, 3.77(3H, both                             s, OMe), 3.85-4.2 (3H, m), 4.25-4.45(1H, m),                             4.55-4.7(1H, m), 4.7- 4.95(1H, m), 5.99,                             6.01(1H, both s), 6.45-6.55(1H, m), 6.84,                             6.92(1H, both brd, J=7.0Hz), 7.2-7.8(6H, m)    5         ##STR137## 1740, 1670 (CO)                             1.29(3H, d, J=7.0Hz), 1.55, 1.56(3H, both d,                             J=6.8Hz), 2.65-3.1(4H, m), 3.6-3.8(6H, m,                             CH.sub.3 x2), 4.25-4.4 (1H, m), 4.7-5.0(2H, m),                             6.00(1H, s), 6.45-6.55(1H, m), 6.8-7.0(1H, m),                             7.2-7.8(6H, m)    6         ##STR138## 1735, 1670 (CO)                             1.15-1.4(9H, m), 1.55, 1.56(3H, both d,                             J=6.8Hz), 1.9- 2.5(4H, m), 2.70(1H, dd, J=14.4,                             6.2Hz), 2.85-3.05 (1H, m), 4.05-4.4(5H, m),                             4.5-4.7(1H, m), 4.7-5.0 (1H, m), 6.00, 6.01(1H,                             both s), 6.50(1H, d, J=2.4Hz), 6.55, 6.64(1H,                             both brd), 7.2-7.8(6H, m)    __________________________________________________________________________

Example 69

By substantially the same synthetic method as in Example 67, compoundslisted in Table 39 and Table 40 were obtained.

                                      TABLE 39    __________________________________________________________________________     ##STR139##    compd.          m.p.          Elemental Analysis (Found)    No. R           (°C.)                          Formula C   H   N    __________________________________________________________________________    1   NHCH.sub.2 CH.sub.2 COOH                    182-184                          C.sub.23 H.sub.24 Cl.sub.2 N.sub.2 O.sub.5                                  57.63                                      5.05                                          5.84                                  (57.36)                                      (5.08)                                          (5.67)         ##STR140## amorphous solid                          C.sub.28 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5                                  62.11 (62.09)                                      4.84 (5.02)                                          5.17 (5.24)    3         ##STR141## 213-215                          C.sub.28 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                  62.71 (62.61)                                      5.08 (4.96)                                          5.04 (5.13)    __________________________________________________________________________

                                      TABLE 40    __________________________________________________________________________    Compd.          m.p.          Elemental Analysis (Found)    No. R           (°C.)                          Formula C   H   N    __________________________________________________________________________         ##STR142## amorphous solid                          C.sub.23 H.sub.24 Cl.sub.2 N.sub.2 O.sub.6                                  55.77 (55.88)                                      4.88 (5.27)                                          5.66 (5.84)    5         ##STR143## amorphous solid                          C.sub.24 H.sub.24 Cl.sub.2 N.sub.2 O.sub.7                                  55.07 (54.65)                                      4.62 (4.98)                                          5.35 (5.22)    6         ##STR144## 198-199                          C.sub.25 H.sub.28 Cl.sub.2 N.sub.2 O.sub.7                                  55.88 (55.97)                                      4.88 (5.16)                                          5.21 (5.16)    __________________________________________________________________________

Example 70

By substantially the same synthetic method as in Reference Example 2, acompound listed in Table 41 was obtained.

                                      TABLE 41    __________________________________________________________________________     ##STR145##                          m.p.          Elemental Analysis (Found)    R.sub.1     R.sub.2   (°C.)                                Formula C   H   N    __________________________________________________________________________     ##STR146##                 ##STR147##                          amorphous solid                                C.sub.33 H.sub.26 Cl.sub.2 N.sub.2 O.sub.4                                        IRν.sub.max.sup.neat cm.sup.-1 :                                        3400(NH), 1740(CO), 1670(CO) .sup.1                                        HNMR(CDCl.sub.3) δ: 2.9(1H,                                        dd), 3.2(1H, dd), 4.47(1H,  dd,                                        C.sub.3H), 5.54(1H, s,    __________________________________________________________________________                                        C.sub.5H)

Also, physicochemical properties of an intermediate are shown in Table42.

Example 71 Ethyl ester oftrans-7-chloro-5-(2,4,6-trimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

(1) 2-acetylamino-5-chloro-2',4',6'-trimethoxybenzophenone

A solution of 2.41 g of 1,3,5-trimethoxybenzene in 10 ml of drytetrahydrofuran was cooled to -78° C., and 9.1 ml of n-butyl lithium(1.58M solution in hexane) was added dropwise over a period of 10minutes. This solution was added dropwise to a solution of 2.0 g of6-chloro-4-methyl-4H-3,1-benzoxazin-4-one in 20 ml of drytetrahydrofuran. After mixture stirring at 0° C. for 1 hour, the solventwas removed, after which the residue was acidified with dilutehydrochloric acid and then extracted with ethyl acetate. After theextract was washed with dilute hydrochloric acid and an aqueous solutionof sodium hydrogen carbonate, the solvent was removed, and the residuewas subjected to silica gel column chromatography to yield 1.28 g of acrystal.

Melting point: 159°-160° C.

Elemental analysis (for C₁₈ H₁₈ ClNO₅) Calcd.: C 59.43; H 4.99; N 3.85Found: C 59.39; H 4.94; N 3.86

(2) 2-amino-5-chloro-2',4'-6'-trimethoxybenzophenone

A mixture of 4.7 g of2-acethylamino-5-chloro-2',4',6'-trimethoxybenzophenone, 50 ml of 6Nhydrochloric acid and 50 ml of ethanol was refluxed for 1 hour whileheating. After the solvent was distilled off, the residue was basefiedwith an aqueous solution of sodium hydrogen carbonate and then extractedwith ethyl acetate. After the extract was washed with water and dried,the solvent was removed, and the residue was subjected to silica gelcolumn chromatography to yield 3.75 g of a crystal.

(3) 2-amino-5-chloro-α-(2,4,6-trimethoxyphenyl)benzyl

                                      TABLE 42    __________________________________________________________________________     ##STR148##                         m.p.          Elemental Analysis (Found)    R.sub.1    R.sub.2   (°C.)                               Formula C   H   N    __________________________________________________________________________     ##STR149##                ##STR150##                         amorphous solid                               C.sub.33 H.sub.20 Cl.sub.2 N.sub.2 O.sub.4                                       1HNMR (CDCl.sub.3)δ: 4.7(1H, d),                                       5.03(2H, s, CH.sub.2 Ph), 5.65(1H, d),                                       6.0-8.3(20H, m)    __________________________________________________________________________

alcohol

To a solution of 3.0 g of2-amino-5-chloro-2',4',6'-trimethoxybenzophenone in 50 ml oftetrahydrofuran, 0.43 g of lithium aluminum hydride was added, followedby stirring for 1 hour. After water was added, the solution wasextracted with ethyl acetate and dried over anhydrous sodium sulfate,after which the solvent was removed and the residue was subjected tosilica gel column chromatography to yield 2.9 g of a crystal.

(4) 5-chloro-α-(2,4,6-trimethoxyphenyl)-2-(neopentylamino)benzyl alcohol

After a solution of 2.5 g of2-amino-5-chloro-α-(2,4,6-trimethoxyphenyl)benzyl alcohol, 1.01 ml oftrimethylacetaldehyde and 0.56 g of acetic acid in 30 ml of ethanol wasstirred at room temperature for 1.5 hours, 0.81 g of sodiumcyanoborohydride was added, followed by stirring overnight. Afterconcentration and subsequent dilution with water, the solution wasextracted with ethyl acetate. After solvent removal, the residue wassubjected to silica gel column chromatography to yield 2.2 g of acrystal.

(5) Ethyl ester of 3-N-(4-chloro-2-(α-hydroxy-2,4,6-trimethoxybenzyl)phenyl!-N-neopentylcarbamoyl!acrylicacid

2.0 g of 5-chloro-α-(2,4,6-trimethoxyphenyl)-2-(neopentylamino)benzylalcohol, 0.99 g of monoethyl ester of chlorofumaric acid and 0.85 g ofsodium hydrogen carbonate were added to 30 ml of dichloromethane, andthis mixture was stirred for 30 minutes. To the reaction mixture wasadded water, and the organic layer was dried, after which the solventwas removed and the residue was subjected to silica gel columnchromatography to yield 2.5 g of an oily compound.

(6) Ethyl ester oftrans-7-chloro-5-(2,4,6-trimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

2.5 g of ethyl ester of 3-N-(4-chloro-2-(α-hydroxy-2,4,6-trimethoxybenzyl)phenyl!-N-neopentylcarbamoyl!acrylicacid and 1.33 g of potassium carbonate were added to 30 ml of ethanol,and this mixture was stirred at room temperature overnight. After ethylacetate was added, the mixture was washed with water and dried, afterwhich the solvent was removed and the residue was subjected to silicagel column chromatography to yield 2.0 g of a crystal.

Melting point: 154°-155° C.

Elemental analysis (for C₂₇ H₃₄ ClNO₇) Calcd.: C 62.36; H 6.59; N 2.69Found: C 62.51; H 6.32; N 2.67

Example 72

By the same procedure as in Example 71, the compounds listed in Tables43 and 44 were obtained.

                                      TABLE 43    __________________________________________________________________________     ##STR151##    Compd.         m.p.        Elemental Analysis (Found)    No. X  Y       (°C.)                        Formula                               C   H   N    __________________________________________________________________________    1   7-Cl           2', 4'-OCH.sub.3                   117-119                        C.sub.26 H.sub.32 ClNO.sub.6                               63.73                                   6.58                                       2.86                               (63.63                                   6.81                                       2.83)    2   7-Cl           2', 6'-OCH.sub.3                   175-177                        C.sub.26 H.sub.32 ClNO.sub.6                               63.73                                   6.58                                       2.86                               (63.54                                   6.49                                       2.89)    3   7-Cl           2', 5'-OCH.sub.3                   165-166                        C.sub.26 H.sub.32 ClNO.sub.6                               63.73                                   6.58                                       2.86                               (63.63                                   6.59                                       2.82)    4   7-Cl           2', 3'-OCH.sub.2 O                   164-167                        C.sub.25 H.sub.28 ClNO.sub.6                               63.35                                   5.95                                       2.96                               (63.31                                   5.88                                       2.92)    5   7-Cl           2', 4'-OCH.sub.2 O                   133-134                        C.sub.25 H.sub.28 ClNO.sub.6                               63.36                                   5.95                                       2.96                               (63.13                                   5.96                                       2.79)    __________________________________________________________________________

                                      TABLE 44    __________________________________________________________________________    Compd.        m.p.         Elemental Analysis (Found)    No. X   Y     (°C.)                       Formula C   H   N    __________________________________________________________________________    6   8-Cl            2'-Cl 142-143                       C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                               62.07                                   5.86                                       3.02                               (61.87                                   6.01                                       2.89)    7   7,9-Cl            2'-OCH.sub.3                  167-169                       C.sub.25 H.sub.29 Cl.sub.2 NO.sub.5                               60.73                                   5.91                                       2.83                               (60.73                                   5.97                                       2.71)    8   7-Cl            2'-OCH.sub.3                  173-174                       C.sub.25 H.sub.30 ClNO.sub.5                               65.28                                   6.57                                       3.05                               (65.32                                   6.64                                       3.11)    9   7-Cl            2'-Br 128-129                       C.sub.24 H.sub.27 BrClNO.sub.4                               56.65                                   5.35                                       2.75                               (56.77                                   5.42                                       2.76)    10  7-Br            2'-Cl 143-146                       C.sub.24 H.sub.27 BrClNO.sub.4                               56.65                                   5.35                                       2.75                               (56.5O                                   5.23                                       2.58)    11  7-Cl            2',3'-OCH.sub.3                  184-185                       C.sub.20 H.sub.32 ClNO.sub.6                               63.73                                   6.58                                       2.86                               (63.75                                   6.82                                       2.67)    __________________________________________________________________________

Example 73

By the same procedure as in Example 71 except that isobutyl aldehyde wasused in place of trimethylacetaldehyde, the compounds listed in Tables45 through 47 were obtained.

                                      TABLE 45    __________________________________________________________________________     ##STR152##    Compd.     m.p.      Elemental Analysis (Found)    No. X   Y  (°C.)                  Formula                         C         H         N    __________________________________________________________________________    1   7-F 2'-Cl               oil                  C.sub.23 H.sub.25 ClFNO.sub.4                         .sup.1 H-NMR(CDCl.sub.3)δ: 0.93 and 1.03(each                         3H, d,                         J=6.6Hz, 1.25(3H, t, J=7.2Hz), 1.86-2.10                         (1H, m), 2.80(1H, dd, J=16.5, 6.2Hz), 3.06(1H, dd,                         J=16.5, 7.4                         Hz), 3.44(1H, dd, J=13.8, 5.4Hz), 4.14(2H, q,                         J=7.2Hz), 4.32                         (1H, dd, J=13.8, 8.4Hz), 4.43(1H, dd, J=7.4, 6.2Hz),                         6.15                         (1H, s), 6.26(1H, dd, J=9.0, 2.9Hz), 7.12(1H, ddd,                         J=8.8, 7.6,                         2.9Hz), 7.29-7.47(4H, m), 7.66-7.75(1H, m)    2   7-OCH.sub.3            2'-Cl               oil                  C.sub.24 H.sub.28 ClNO.sub.5                         .sup.1 HNMR(CDCl.sub.3)δ: 0.93(3H, d,                         J=6.8Hz), 1.03                         (3H, d, J=6.6Hz), 1.25(3H, t, J=7.2Hz), 1.98                         (1H, m), 2.80(1H, dd, J=6.2, 16.4Hz), 3.04(1H, dd,                         J=7.2, 16.4Hz),                         3.43(1H, dd, J=5.4, 13.6Hz), 3.6(3H, s), 4.13(2H, q,                         J=7.2Hz),                         4.30(1H, dd, J=8.4, 13.6Hz), 4.44(1H, dd, J=6.2,                         7.2Hz), 6.06                         (1H, d, J=3.0Hz), 6.16(1H, s), 6.93(1H, dd, J=3.0,                         8.6Hz), 7.25-                         7.74(5H, m)    __________________________________________________________________________

                                      TABLE 46    __________________________________________________________________________    Compd.        m.p.            Elemental Analysis (Found)    No. X   Y     (°C.)                        Formula   C     H    N    __________________________________________________________________________    3   7-Cl            2',4'-Cl                  amorphous                        C.sub.23 H.sub.24 Cl.sub.3 NO.sub.4                                  56.98 4.99 2.89                  solid (56.92    5.00  2.95)    4   7-Cl            2'-CF.sub.3                  120-122                        C.sub.24 H.sub.25 ClF.sub.3 NO.sub.4                                  59.57 5.21 2.89                                  (59.57                                        5.18 2.84)    5   7-Cl            2-OCH.sub.3                  124-125                        C.sub.24 H.sub.28 ClNO.sub.5                                  64.64 6.33 3.11                                  (64.54                                        6.34 3.07)    6   7-Cl            2'-Br oil   C.sub.23 H.sub.25 BrClNO.sub.4                                  .sup.1 H-NMR(CDCl.sub.3)δ: 0.95 (3H,                                  d, J=6.8 Hz), 1.06                                  (3H, d, J=6.6 Hz), 1.25(3H, t, J=7.1 Hz),                                  1.85-                        2.09(1H, m), 2.80(1H, dd, J=16.6.6.2 Hz), 3.05(1H,                        dd, 1=16.6.                        7.4 Hz), 3.48(1H, dd, J=13.8.5.2 Hz), 4.14(2H, q,                        J=7.1 Hz), 1.29                        (1H, dd, J=13.8.8.8 Hz), 4.43(1H, dd, J=7.4.6.2 Hz),                        6.07(1H, s),                        6.50(1H, d, J=2.2 Hz), 7.22-7.75(6H, m)    7   7-Br            2'-Cl oil   C.sub.23 H.sub.25 BrClNO.sub.4                                  .sup.1 H-NNR(COCl.sub.3)δ: 0.93 and                                  1.02(each 3H, d,                                  J=6.6 Hz), 1.25(3H, t, J=7.2 Hz),                                  1.86-2.08                        (1H, m), 2.79(1H, dd, J=16.6.6.2 Hz), 3.06(1H, dd,                        J=16.6.7.1 Hz),                        3.44(1H, dd, J=13.8.5.6 Hz), 4.13(2H, q, J=7.2Hz),                        4.31(1H, dd, J=                        13.8.8.4 Hz), 4.43(1H, dd, J=7.4.6.2 Hz), 6.13(1H,                        s), 6.65(1H, d,                        J=2.4 Hz), 7.20-7.75(6H, m)    __________________________________________________________________________

                                      TABLE 47    __________________________________________________________________________    Compd.        m.p.            Elemental Analysis (Found)    No. X   Y     (°C.)                        Formula   C     H    N    __________________________________________________________________________     8  7-Cl            4'-Cl oil   C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                                  .sup.1 H-NNR(CDCl.sub.3)δ: 0.91 and                                  0.98(each 3H, d, J=                                  6.6 Hz), 1.24(3H, t, J=7.1 Hz),                                  1.93-2.20(1H, m)                        2.76(1H, dd, J=16.6.60 Hz), 3.05(1H, dd, J=16.6.7.6                        Hz), 3.44                        (1H, dd, J=13.6.7.6 Hz), 4.12(2H, q, J=7.1 Hz),                        1.26(1H, dd, J=13.6                        .7.6Hz), 4.41(1H, dd, J=7.6.6.0 Hz), 5.84(1H, s),                        6.57(1H, s),                        7.20-7.50(6H, m)     9  H   2'-CH.sub.3                  88-90 C.sub.24 H.sub.29 NO.sub.4                                  72.89 7.39 3.51                                  (73.18                                        7.25 3.54)    10  7-Cl            3'-Cl oil   C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                                  .sup.1 H-NMR(CDCl.sub.3)δ: 0.91(3H,                                  d, J=20 Hz), 0.98(3H,                                  d, J=6.6 Hz), 1.25 (3H, t, J=7.1 Hz),                                  1.95-2.18                        (1H, m), 2.78(1H, dd, J=16.4.6.0 Hz), 3.05 (1H, dd,                        J=16.1.7.6 Hz)m                        3.44(1H, dd, J=13.6.6.4 Hz), 4.13(2H, q, J=7.1 Hz),                        4.26(1H, dd, J=                        13.6.7.6 Hz,. 4.40(1H, dd, J=7.6.6.0 Hz), 5.84(1H,                        s), 6.59(1H, d,                        J=2.0 Hz), 7.14-7.50(6H, m)    11  7-CF.sub.3            H     100-102                        C.sub.24 H.sub.26 F.sub.3 NO.sub.4                                  64.13 5.83 3.12                                  (64.44                                        5.85 2.98)    12  7-Cl            H     oil   C.sub.23 H.sub.21 ClNO.sub.4                                  .sup.1 H-NMR(CDCl.sub.3)δ:0.91 and                                  0.99(each 3H, d, J=                                  6.6 Hz), 1.24(3H, t, J=7.2 Hz),                                  1.95-2.20(1H, m)                        2.78(1H, dd, J=16.6.5.8 Hz), 3.07(1H, dd, J=16.6.7.8                        Hz), 3.44                        (1H, dd, J=13.8.6.4 Hz), 4.13(2H, q, J=7.2 Hz),                        4.27(1H, dd, J=13.8                        7.6 Hz), 4.43(1H, d, J=7.5.8 Hz), 5.88(1H, s),                        6.61(1H, d, J=2.4                        Hz), 7.24-7.49(7H, m)    __________________________________________________________________________

Example 74

The compounds obtained in Examples 71 and 72 were hydrolyzed by the sameprocedure as in Reference Examples 5 and Example 2 to yield thecompounds listed in Tables 48 and 49.

                                      TABLE 48    __________________________________________________________________________     ##STR153##    Compd.         m.p.         Elemental Analysis (Found)    No. X  Y       (°C.)                        Formula C   H   N    __________________________________________________________________________    1   7-Cl           2',4'-OCH.sub.3                   260-263                        C.sub.24 H.sub.28 ClNO.sub.6                                62.40                                    6.11                                        3.03                                (62.27                                    6.26                                        2.97)    2   7-Cl           2',6'-OCH.sub.3                   263-270                        C.sub.24 H.sub.28 ClNO.sub.6 +                                61.68                                    6.17                                        3.00                   (decomp)                        0.3H.sub.2 O                                (61.72                                    6.15                                        2.90)    3   7-Cl           2',5'-OCH.sub.3                   230-232                        C.sub.24 H.sub.28 ClNO.sub.6                                62.40                                    6.11                                        3.03                                (62.31                                    6.13                                        3.03)    4   7-Cl           2',4',6'-                   260-263                        C.sub.25 H.sub.30 ClNO.sub.7                                61.04                                    6.15                                        2.85           OCH.sub.3                   (decomp)     (60.97                                    6.12                                        2.71)    5   7-Cl           2',3'-OCH.sub.2 O                   215-218                        C.sub.23 H.sub.24 ClNO.sub.6                                61.95                                    5.42                                        3.14                                (61.78                                    5.56                                        3.31)    __________________________________________________________________________

                                      TABLE 49    __________________________________________________________________________    Compd.         m.p.         Elemental Analysis (Found)    No. X   Y      (°C.)                        Formula C   H   N    __________________________________________________________________________    6   7-Cl            3',4'-OCH.sub.2 O--                   211-212                        C.sub.23 H.sub.24 ClNO.sub.6                                61.95                                    5.43                                        3.14                                (61.79                                    5.37                                        2.94)    7   8-Cl            2'-Cl  186-181                        C.sub.22 H.sub.23 Cl.sub.2 NO.sub.4                                60.56                                    5.31                                        3.21                                (60.23                                    5.58                                        3.06)    8   7,9-Cl            2'-OCH.sub.3                   265-267                        C.sub.23 H.sub.25 Cl.sub.2 NO.sub.5                                58.12                                    5.51                                        2.94                        +0.5H.sub.2 O                                (58.18                                    5.27                                        2.69)    9   7-Cl            2'-OCH.sub.3                   167-168                        C.sub.23 H.sub.20 ClNO.sub.5                                63.96                                    6.07                                        3.24                                (63.56                                    6.11                                        3.07)    10  7-Cl            2'-Br  251-253                        C.sub.22 H.sub.23 BrClNO.sub.4                                54.96                                    4.82                                        2.91                                (54.97                                    4.85                                        2.87)    11  7-Br            2'-Cl  247-250                        C.sub.22 H.sub.23 BrClNO.sub.4                                54.96                                    4.82                                        2.91                                (54.73                                    5. 12                                        2.82)    12  7-Cl            2',3'-OCH.sub.3                   244-247                        C.sub.24 H.sub.28 ClNO.sub.6                                61.68                                    6.17                                        3.00                        +0.3H.sub.2 O                                (61.65                                    6.16                                        2.89)    __________________________________________________________________________

Example 75

The compounds obtained in Example 73 were hydrolyzed by the sameprocedure as in Reference Example 5 and Example 2 to yield the compoundslisted in Tables 50 and 51.

                                      TABLE 50    __________________________________________________________________________     ##STR154##    Compd.       m.p.          Elemental Analysis (Found)    No. X    Y   (°C.)                      Formula  C   H   N    __________________________________________________________________________    1   7-F  2'-Cl                 204-206                      C.sub.21 H.sub.21 ClFNO.sub.4                               62.15                                   5.22                                       3.45                               (61.96                                   5.18                                       3.66)    2   7-OCH.sub.3             2'-Cl                 92-94                      C.sub.22 H.sub.24 ClNO.sub.5 +                               62.16                                   5.88                                       3.30                      0.4H.sub.2 O                               (62.14                                   5.93                                       3.28)    3   7-Cl 2',4'-Cl                 236-238                      C.sub.21 H.sub.20 Cl.sub.3 NO.sub.4                               55.22                                   4.41                                       3.07                               (55.12                                   4.45                                       3.00)    4   7-Cl 2'-CF.sub.3                 212-225                      C.sub.22 H.sub.21 ClF.sub.3 NO.sub.4                               57.97                                   4.64                                       3.07                               (57.72                                   4.67                                       3.05)    __________________________________________________________________________

                                      TABLE 51    __________________________________________________________________________    Compd.        m.p.         Elemental Analysis (Found)    No. X   Y     (°C.)                       Formula C   H   N    __________________________________________________________________________    5   7-Cl            2'-OCH.sub.3                  219-222                       C.sub.22 H.sub.24 ClNO.sub.5                               63.23                                   5.79                                       3.35                               (62.88                                   6.09                                       3.16)    6   7-Cl            2'-Br 212-216                       C.sub.21 H.sub.21 BrClNO.sub.4                               54.04                                   4.53                                       3.00                               (53.68                                   4.56                                       3.10)    7   7-Br            2'-Cl 194-196                       C.sub.21 H.sub.21 BrClNO.sub.4                               53.61                                   4.59                                       2.98                       +0.2H.sub.2 O                               (53.44                                   1.49                                       2.91)    8   7-Cl            4'-Cl 223-225                       C.sub.21 H.sub.21 Cl.sub.2 NO.sub.4                               59.73                                   5.01                                       3.32                               (59.58                                   5.01                                       3.23)    9   H   2'-CH.sub.3                  192-195                       C.sub.22 H.sub.25 NO.sub.4                               71.91                                   6.86                                       3.81                               (71.86                                   6.78                                       3.80)    10  7-Cl            3'-Cl 158-160                       C.sub.21 H.sub.21 Cl.sub.2 NO.sub.4                               59.22                                   5.06                                       3.29                       +0.2H.sub.2 O                               (59.00                                   5.00                                       3.23)    11  7-CF.sub.3            H     149-151                       C.sub.22 H.sub.22 F.sub.3 NO.sub.4                               62.70                                   5.26                                       3.32                               (62.51                                   5.50                                       3.14)    12  7-Cl            H     190-192                       C.sub.21 H.sub.22 ClNO.sub.4                               65.03                                   5.72                                       3.61                               (64. 94                                   5.61                                       3.18)    __________________________________________________________________________

Example 76 n-butyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

A solution of 0.4 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2, 0.21 ml of n-butyl iodide and 0.21 ml oftriethylamine in 5 ml of dimethylformamide was stirred overnight at roomtemperature. After ethyl acetate was added, the mixture was washed withdilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and water. After the solution was dried, the solvent wasremoved and the residue was subjected to silica gel columnchromatography to yield 0.25 g of a crystal.

Melting point: 106°-109° C.

Elemental analysis (for C₂₆ H₃₁ Cl₂ NO₄) Calcd.: C 63.42; H 6.35; N 2.84Found: C 63.42; H 6.39; N 2.71

Example 77

By the same procedure as in Example 76, the compounds listed in Tables52 through 54 were synthesized.

                                      TABLE 52    __________________________________________________________________________     ##STR155##    Compd.           m.p.       Elemental Analysis (Found)    No. R            (°C.)                        Formula C         H         N    __________________________________________________________________________         ##STR156##  oil                        C.sub.28 H.sub.34 Cl.sub.2 NO.sub.6                                .sup.1 HNMR(CDCl.sub.3)δ: 0.93(9H, s,                                Bu'), 1.19(9H, s, Bu'), 2.86(1H, dd, J=16.8,                                6.4Hz), 3.09(1H, dd, J=16.6, 7.0Hz), 4.27(1H,                                t, J=6.8Hz), 4.50(1H, d, J=14.0Hz), 5.73(1H,                                d, J=15.0Hz), 5.79(1H, d, J=15.0Hz), 6.26(1H,                                s, C.sub.5H), 6.5-6.6(1H, m), 7.3-7,8(6H, m,                                aromatic)    2         ##STR157##  oil                        C.sub.31 H.sub.37 Cl.sub.2 NO.sub.7                                .sup.1 HNMR(CDCl.sub.3)δ: 0.93(9H, s,                                Bu'), 1.1-1.6 (6H, m), 1.65-2.0(4H, m),                                2.75-3.2(2H, m), 3.3- 3.5(1H, m),                                4.35-4.7(3H, m), 6.25 and 6.28(1H, each s,                                C.sub.5H), 6.52(1H, s, aromatic),                                6.7-6.85(1H, m), 7.3-7.8(6H, m,    __________________________________________________________________________                                aromatic)

                                      TABLE 53    __________________________________________________________________________    Compd.            m.p.         Elemental Analysis (Found)    No. R             (°C.)                           Formula C         H         N    __________________________________________________________________________         ##STR158##   oil  C.sub.32 H.sub.39 Cl.sub.2 NO.sub.6                                   .sup.1 HNMR(CDCl.sub.3)δ: 0.93(6H,                                   d, J=6.8Hz), 0.94 (9H, s, Bu'), 1.06(3H,                                   t, J=7.6Hz), 1.85-2.1 (1H, m), 2.2-2.4(2H,                                   m), 2.81(1H, dd, J=16.6, 6.8Hz), 3.02(1H,                                   dd, J=16.6, 6.8Hz), 3.39(1H, d, J=14.0Hz),                                   3.92(2H, d, J=6.6 Hz), 4.42(1H, t,                                   J=6.7Hz), 4.50(1H, d, J=14.0Hz), 4.81(1H,                                   d, J=11.6Hz), 4.93(1H, d, J=11.6Hz),                                   6.25(1H, s, C.sub.5H), 6.52(1H, s),                                   7.04(1H, t, J=7.8Hz), 7.3-7.8(6H, m)    4         ##STR159##   167-168                           C.sub.26 H.sub.30 Cl.sub.2 N.sub.2 O.sub.5                                   59.89 (59.92                                             5.80 5.82 5.37 5.15)    5         ##STR160##   oil  C.sub.30 H.sub.38 Cl.sub.2 N.sub.2 O.sub.5                                   .sup.1 HNMR(CDCl.sub.3)δ: 0.94(9H,                                   s, Bu'), 1.1-1.5 (12H, m), 2.99(1H, dd,                                   J=16.8, 6.1Hz), 3.20 (1H, dd, J=16.8,                                   7.2Hz), 3.39(1H, d, J=14.0Hz), 3.3-3.8(2H,                                   m), 4.4-4.65(3H, m), 4.78(1H, d,                                   J=14.0Hz), 6.27(1H, s), 6.52(1H, s),                                   7.3-7.8(6H, m)    6         ##STR161##   165-166                           C.sub.27 H.sub.27 Cl.sub.2 NO.sub.7                                   59.13 (59.21                                             4.96 5.28 2.55 2.46)    7         ##STR162##   191-193                           C.sub.32 H.sub.29 Cl.sub.2 NO.sub.6                                   64.65 (64.67                                             4.92 5.27 2.36 2.14)    __________________________________________________________________________

                                      TABLE 54    __________________________________________________________________________    Compd.          m.p.         Elemental Analysis (Found)    No. R           (°C.)                         Formula C   H   N    __________________________________________________________________________    8   CH.sub.3    158-159                         C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                                 61.34                                     5.60                                         3.11                                 (61.48                                     5.78                                         2.84)         ##STR163## 122-123                         C.sub.29 H.sub.29 Cl.sub.2 NO.sub.4. 1/2H.sub.2                                 65.54 (65.40                                     5.69 5.70                                         2.64 2.43)    10  CH.sub.2 COOCH.sub.3                    137-138                         C.sub.25 H.sub.27 Cl.sub.2 NO.sub.6                                 59.06                                     5.35                                         2.76                                 (59.11                                     5.34                                         2.60)    11  CH.sub.2 CHCH.sub.2                    108-109                         C.sub.26 H.sub.27 Cl.sub.2 NO.sub.4                                 63.03                                     5.71                                         2.94                                 (63.12                                     5.86                                         2.77)    12         ##STR164## 89-90                         C.sub.29 H.sub.35 Cl.sub.2 NO.sub.4                                 65.41 (65.62                                     6.62 6.51                                         2.63 2.42)    13  CH.sub.2 COOC(CH.sub.3).sub.3                    140  C.sub.28 H.sub.33 Cl.sub.2 NO.sub.6                                 61.09                                     6.04                                         2.54                                 (60.87                                     6.14                                         2.48)    __________________________________________________________________________

Example 78 Phenyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

0.3 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 and 0.072 g of phenol were dissolved in 12ml of dichloromethane, and 10 ml of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added,followed by stirring at room temperature for 1.5 hours. The reactionmixture was concentrated, ethyl acetate was added and the mixture waswashed with water, after which the organic layer was dried and thesolvent was distilled off. The residue was subjected to silica gelcolumn chromatography to yield 0.28 g of a crystal.

Melting point: 147°-148° C.

Elemental analysis (for C₂₈ H₂₇ Cl₂ NO₄) Calcd.: C 65.63; H 5.31; N 2.73Found: C 65.55; H 5.45; N 2.46

Example 79

The compounds obtained in Example 2 were subjected to the same procedureas in Example 78 to yield the compounds listed in Table 55.

                                      TABLE 55    __________________________________________________________________________     ##STR165##    Compd.           m.p.         Elemental Analysis (Found)    No. R            (°C.)                          Formula C   H   N    __________________________________________________________________________         ##STR166##  199-200                          C.sub.31 H.sub.31 Cl.sub.2 NO.sub.4                                  63.70 (63.71                                      5.35 5.63                                          2.40 2.11)    2         ##STR167##  100-101                          C.sub.25 H.sub.29 Cl.sub.2 NO.sub.4                                  62.76 (62.91                                      6.11 6.32                                          2.93 2.72)    __________________________________________________________________________

Example 80 Cyclohexylthio ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

0.3 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 and 0.09 g of cyclohexylmercaptan weresubjected to the same procedure as in Example 78 to yield 0.19 g of acrystalline compound.

Melting point: 157°-158° C.

Elemental analysis (for C₂₈ H₃₃ Cl₂ NO₃ S) Calcd.: C 62.91; H 6.22; N2.62 Found: C 62.94; H 6.08; N 2.40

Example 81 t-butyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

To a solution of 1.2 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 in 40 ml of dichloromethane, 10 ml ofisobutene and 0.1 ml of concentrate sulfuric acid were added, and themixture was kept standing at room temperature for 3 days. After reactionmixture concentration, ethyl acetate and an aqueous solution of sodiumhydrogen carbonate were added, and the organic layer was washed withwater and dried, after which the solvent was removed and the residue wassubjected to silica gel column chromatography to yield 1.07 g of acrystal.

Melting point: 141°-142° C.

Elemental analysis. (for C₂₆ H₃₁ ClNO₄) Calcd.: C 63.42; H 6.35; N 2.84Found: C 63.52; H 6.37; N 2.80

Example 82 Carboxymethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

0.3 g of t-butoxycarbonylmethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 77 was dissolved in 3 ml of trifluoroaceticacid, and this solution was kept standing at room temperature for 30minutes. After the solution was concentrated, ethyl acetate was added,followed by washing with water and subsequent drying, after which thesolvent was removed and the residue was recrystallized from petroleumether to yield 0.24 g of a crystal.

Melting point: 186°-190° C.

Elemental analysis (for C₂₄ H₂₅ Cl₂ NO₆.1/2H₂.O) Calcd.: C 57.27; H5.21; N 2.78 Found: C 57.38; H 5.05; N 2.78

Example 83 Methyl ester of 2-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminobenzoicacid

0.35 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Reference Example 5 was dissolved in 10 ml oftoluene, and 0.63 ml of thionyl chloride was added, followed by stirringfor 30 minutes while heating at 90° C. The solution was concentrated andthe residue was dissolved in 10 ml of dichloromethane, and 0.13 ml ofmethyl ester of 2-aminobenzoic acid and 0.14 ml of triethylamine wereadded, followed by stirring at room temperature for 30 minutes. Afterthe solution was concentrated, ethyl acetate was added, and the mixturewas washed with dilute hydrochloric acid, an aqueous solution of sodiumhydrogen carbonate and water. The solvent was removed and the residuewas subjected to silica gel column chromatography to yield 0.25 g of acrystal.

Melting point: 188°-190° C.

Elemental analysis (for C₂₈ H₂₆ Cl₂ N₂ O₅) Calcd.: C 62.11; H 4.91; N5.24 Found: C 61.94; H 4.91; N 5.24

Example 84

By the same procedure as in Example 83, the compounds listed in Tables56 and 57 were obtained.

                                      TABLE 56    __________________________________________________________________________     ##STR168##    Compd.            m.p.         Elemental Analysis (Found)    No. R             (°C.)                           Formula C   H   N    __________________________________________________________________________         ##STR169##   161-163                           C.sub.29 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                   62.71 (62.62                                       5.08 4.96                                           5.04 5.15)    2         ##STR170##   236-238                           C.sub.29 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                   62.71 (62.67                                       5.08 5.26                                           5.04 5.09)    3         ##STR171##   172-174                           C.sub.29 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                   62.71 (62.63                                       5.08 5.00                                           5.04 5.28)    4         ##STR172##   92-94                           C.sub.29 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5.                           1/2H.sub.2 O                                   61.71 (61.85                                       5.18 5.33                                           4.96 5.10)    __________________________________________________________________________

                                      TABLE 57    __________________________________________________________________________    Compd.                m.p.         Elemental Analysis (Found)    No. R                 (°C.)                               Formula C        H         N    __________________________________________________________________________         ##STR173##       139-142                               C.sub.29 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                       62.71 (62.62                                                5.08 5.12 5.04 4.96)    6         ##STR174##       oil  C.sub.38 H.sub.38 Cl.sub.2 N.sub.2 O.sub.5                                       .sup.1 H-NMR(CDCl.sub.3)δ:                                       1.27(9H, s, Bu'), 1.29(3H,                                       d, J=6.8Hz), 1.54(3H, d, J=6.8Hz),                                       2.71(1H, dd, J=14.2, 6.0Hz), 2.95(1H,                                       dd, J=14.2, 7.4Hz), 4.38(1H, t, J=                                       6.6Hz), 4.45-4.6(1H, m), 4.7-4.9(2H,                                       m), 6.00(1H, s), 6.3-6.45 (1H, m, NH),                                       6.50(1H, d, J=2.4Hz), 7.2-7.85(14H,    __________________________________________________________________________                                       m)

Example 85 2-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminobenzoicacid

0.15 g of methyl ester of 2-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminobenzoicacid as obtained in Example 83 was subjected to the same procedure ofester hydrolysis as in Example 34 to yield 0.11 g of a crystal.

Melting point: 208°-211° C.

Elemental analysis (for C₂₇ H₂₄ Cl₂ N₂ O₅) Calcd.: C 61.49; H 4.59; N5.31 Found: C 61.22; H 4.68; N 5.35

Example 86

The compounds obtained in Example 84 were subjected to the sameprocedure of ester hydrolysis as in Example 34 to yield the compoundslisted in Table 58.

                                      TABLE 58    __________________________________________________________________________     ##STR175##    Compd.            m.p.            Elemental Analysis (Found)    No. R             (°C.)                           Formula    C   H   N    __________________________________________________________________________         ##STR176##   149-152                           C.sub.27 H.sub.24 Cl.sub.2 N.sub.2 O.sub.5                                      61.49 (61.81                                          4.59 4.79                                              5.31 5.45)    2         ##STR177##   >300 C.sub.27 H.sub.24 Cl.sub.2 N.sub.2 O.sub.5.1/4H.sub                           .2 O       60.97 (60.97                                          4.64 4.76                                              5.27 5.39)    3         ##STR178##   223-225                           C.sub.28 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5                                      62.11 (61.96                                          4.84 4.82                                              5.17 5.35)    4         ##STR179##   240-244                           C.sub.28 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5                                      62.11 (62.13                                          4.84 5.00                                              5.17 5.17)    5         ##STR180##   242-244 (decomp)                           C.sub.28 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5                                      62.11 (61.96                                          4.84 4.85                                              5.17 5.25)    __________________________________________________________________________

Example 87 Ethyl ester of 4-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminobenzoicacid

0.6 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 and 0.27 g of ethyl ester of4-aminobenzoic acid were subjected to the same procedure as in Example83 to yield 0.43 g of a crystal.

Melting point: 218°-210° C.

Elemental analysis (for C₃₁ H₃₂ Cl₂ N₂ O₅) Calcd.: C 63.81; H 5.53; N4.80 Found: C 63.79; H 5.38; N 4.70

Example 88

By the same procedure as in Example 83, the compounds listed in Tables59 and 60 were synthesized.

                                      TABLE 59    __________________________________________________________________________     ##STR181##    Compd.               m.p.         Elemental Analysis (Found)    No. R                (°C.)                              Formula C   H   N    __________________________________________________________________________         ##STR182##      181-182                              C.sub.31 H.sub.32 Cl.sub.2 N.sub.2 O.sub.5                                      63.81 (63.85                                          5.53 5.41                                              4.80 4.66)    2         ##STR183##      208-209                              C.sub.31 H.sub.32 Cl.sub.2 N.sub.2 O.sub.5                                      63.81 (63.62                                          5.53 5.53                                              4.80 4.79)    3         ##STR184##      224-225                              C.sub.31 H.sub.32 Cl.sub.2 N.sub.2 O.sub.5                                      63.81 (63.69                                          5.53 5.60                                              4.80 4.54)    4         ##STR185##      114-115                              C.sub.32 H.sub.34 Cl.sub.2 N.sub.2 O.sub.5                                      64.32 (64.22                                          5.74 5.97                                              4.69 4.43)    __________________________________________________________________________

                                      TABLE 60    __________________________________________________________________________                                  m.p.    Elemental Analysis (Found)    Compd. No.          R                       oil                                     Formula                                          C       H       N    __________________________________________________________________________           ##STR186##             oil                                     .sup.1 H-NMR(CDCl.sub.3)δ:                                     0.94(9H, s, Bu.sup.1), 1.27(9H, s,                                     Bu.sup.1), 2.72(1H, dd, J=14.2, 6.0Hz),                                     2.92(1H, dd, J=14.2, 7.2Hz), 3.40(1H, d,                                     J=14.0Hz), 4.30-4.7(4H, m), 6.27(1H, s),                                     5.52(1H, d, J=1.6Hz), 7.1-7.9(14H,    __________________________________________________________________________                                     m)

Example 89

The compounds synthesized in Examples 87 and 88 were subjected to thesame procedure as in Examples 24 and 82 to yield the compounds listed inTables 61 and 62.

                                      TABLE 61    __________________________________________________________________________     ##STR187##    Compd.            m.p.         Elemental Analysis (Found)    No. R             (°C.)                           Formula C   H   N    __________________________________________________________________________         ##STR188##   283-286                           C.sub.29 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5                                   62.71 (62.95                                       5.08 5.39                                           5.04 5.01)    2         ##STR189##   220-223                           C.sub.30 H.sub.30 Cl.sub.2 N.sub.2 O.sub.5                                   63.27 (63.24                                       5.31 5.23                                           4.92 4.78)    3         ##STR190##   251-253                           C.sub.30 H.sub.30 Cl.sub.2 N.sub.2 O.sub.5                                   63.27 (62.98                                       5.31 5.43                                           4.92 4.61)    4         ##STR191##   156-158                           C.sub.30 H.sub.30 Cl.sub.2 N.sub.2 O.sub.5                                   63.27 (63.39                                       5.31 5.21                                           4.92 4.76)    __________________________________________________________________________

                                      TABLE 62    __________________________________________________________________________    Compd.                 m.p.         Elemental Analysis (Found)    No. R                  (°C.)                                Formula C   H   N    __________________________________________________________________________         ##STR192##        143-145                                C.sub.31 H.sub.32 Cl.sub.2 N.sub.2 O.sub.5                                1/2H.sub.2 O                                        62.28 (62.32                                            5.61 5.78                                                4.73 4.49)    6         ##STR193##        158-161                                C.sub.36 H.sub.36 Cl.sub.2 N.sub.2 O.sub.5                                        66.77 (66.76                                            5.60 5.80                                                4.33 4.39)    __________________________________________________________________________

Example 90Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide

1.0 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid and 0.5 g of ammonium chloride were dissolved in 8 ml ofdimethylformamide, and 0.46 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7 mlof triethylamine were added, followed by stirring at room temperaturefor 30 minutes. After water was added, the solution was extracted withethyl acetate, followed by washing with water, after which the solventwas removed and the residue was recrystallized to yield 0.75 g of acrystal.

Melting point: 271°-272° C.

Elemental analysis (for C₂₁ H₂₂ Cl₂ N₂ O₃) Calcd.: C 59.87; H 5.26; N6.65 Found: C 59.91; H 5.33; N 6.91

Example 91

The compound obtained in Example 2 and Reference Example 5 and variousamines were subjected to the same procedure as in Example 90 to yieldthe compounds listed in Tables 63 through 67.

                                      TABLE 63    __________________________________________________________________________     ##STR194##    Compd.           m.p.         Elemental Analysis (Found)    No. R.sup.1   R.sup.2                     (°C.)                          Formula C   H   N    __________________________________________________________________________    1   CH(CH.sub.3).sub.2                  NH.sub.2                     226-227                          C.sub.20 H.sub.20 Cl.sub.2 N.sub.2 O.sub.3                                  58.98                                      4.95                                          6.88                                  (58.93                                      4.85                                          6.75)    2   CH.sub.3  NH.sub.2                     187-189                          C.sub.18 H.sub.16 Cl.sub.2 N.sub.2 O.sub.3                                  56.34 (58.53                                      4.33 4.55                                          7.30 6.94)         ##STR195##                  NH.sub.2                     246-248                          C.sub.24 H.sub.26 Cl.sub.2 N.sub.2 O.sub.3                                  62.48 (62.28                                      5.68 5.87                                          6.07 5.86)    4         ##STR196##                  NH.sub.2                     185-187                          C.sub.24 H.sub.20 Cl.sub.2 N.sub.2 O.sub.3                                  62.11 (63.23                                      4.43 4.49                                          6.15 6.10)    __________________________________________________________________________

                                      TABLE 64    __________________________________________________________________________    Compd.                 m.p.         Elemental Analysis (Found)    No. R.sup.1       R.sup.2                           (°C.)                                Formula C   H   N    __________________________________________________________________________         ##STR197##   NHCH.sub.3                           189-190                                C.sub.25 H.sub.22 Cl.sub.2 N.sub.2 O.sub.3                                        63.97 (64.01                                            4.72 4.53                                                5.97 5.90)    6         ##STR198##   N(CH.sub.3).sub.2                           183-184                                C.sub.26 H.sub.24 Cl.sub.2 N.sub.2 O.sub.3.                                1/4H.sub.2 O                                        64.00 (63.97                                            5.06 5.03                                                5.74 5.81)    7         ##STR199##   NHCH.sub.3                           104-107                                C.sub.26 H.sub.24 Cl.sub.2 N.sub.2 O.sub.4.                                1/2H.sub.2 O                                        61.42 (61.65                                            4.96 5.05                                                5.51 5.40)    8         ##STR200##   NHCH.sub.3                           193-195                                C.sub.26 H.sub.24 Cl.sub.2 N.sub.2 O.sub.3                                        64.60 (64.42                                            5.00 4.99                                                5.80 5.73)    9         ##STR201##   NHCH.sub.3                           171-172                                C.sub.26 H.sub.24 Cl.sub.2 N.sub.2 O.sub.4                                        62.53 (62.24                                            4.84 5.05                                                5.61 5.34)    10         ##STR202##   NHCH.sub.3                           190-191                                C.sub.29 H.sub.24 Cl.sub.2 N.sub.2 O.sub.3                                        67.06 (66.78                                            4.66 4.56                                                5.39 5.26)    11  CH.sub.2 CH(CH.sub.3).sub.2                      N(CH.sub.3).sub.2                           134-135                                C.sub.23 H.sub.26 Cl.sub.2 N.sub.2 O.sub.3                                        61.47                                            5.83                                                6.23                                        (61.33                                            5.76                                                6.18)    __________________________________________________________________________

                                      TABLE 65    __________________________________________________________________________    Compd.                     m.p.         Elemental Analysis (Found)    No. R.sup.1   R.sup.2      (°C.)                                    Formula C   H   N    __________________________________________________________________________    12  CH.sub.2 CH(CH.sub.3).sub.2                   ##STR203##  135-136                                    C.sub.25 H.sub.30 Cl.sub.2 N.sub.2                                    O.sub.3 62.89 (63.15                                                6.33 6.38                                                    5.87 5.87)    13  CH.sub.2 CH(CH.sub.3).sub.2                   ##STR204##  168-169                                    C.sub.28 H.sub.28 Cl.sub.2 N.sub.2                                    O.sub.3 65.76 (65.89                                                5.52 5.67                                                    5.48 5.57)    14         ##STR205##                   ##STR206##  141-142                                    C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                    O.sub.3. 1/2H.sub.2 O                                            68.28 (68.33                                                5.04 5.12                                                    4.83 4.65)    15         ##STR207##                   ##STR208##  177-178                                    C.sub.33 H.sub.28 Cl.sub.2 N.sub.2                                    O.sub.4 66.79 (66.97                                                4.90 4.91                                                    4.87 4.83)    16         ##STR209##                   ##STR210##  177-179                                    C.sub.35 H.sub.33 Cl.sub.2 N.sub.3                                    O.sub.3 68.40 (68.35                                                5.41 5.57                                                    6.84 6.82)    17  CH.sub.2 C(CH.sub.3).sub.3                  NHNH.sub.2   248-250                                    C.sub.22 H.sub.25 Cl.sub.2 N.sub.3                                    O.sub.3 58.67                                                5.60                                                    9.33                                            (58.76                                                5.90                                                    8.93)    18  CH.sub.2 C(CH.sub.3).sub.3                  NHN(CH.sub.3).sub.2                               232-235                                    C.sub.24 H.sub.29 Cl.sub.2 N.sub.3                                    O.sub.3 60.25                                                6.11                                                    8.78                                            (60.14                                                6.20                                                    8.51)    __________________________________________________________________________

                                      TABLE 66    __________________________________________________________________________    Compd.            m.p.         Elemental Analysis (Found)    No. R.sup.1               R.sup.2                      (°C.)                           Formula C   H   N    __________________________________________________________________________    19  CH.sub.2 CH(CH.sub.3).sub.2                ##STR211##                      270-271                           C.sub.22 H.sub.22 Cl.sub.2 N.sub.6 O.sub.3.                           1/4H.sub.2 O                                   53.50 (53.63                                       4.59 4.43                                           17.02 16.88)    20  CH(CH.sub.3).sub.2                ##STR212##                      247-248                           C.sub.22 H.sub.23 Cl.sub.2 N.sub.3 O.sub.4                                   56.91 (56.69                                       4.99 4.90)                                           9.05 8.96)    21  CH.sub.2 CH(CH.sub.3).sub.2               NH.sub.2                      271-272                           C.sub.21 H.sub.22 Cl.sub.2 N.sub.2 O.sub.3                                   59.87                                       5.26                                           6.65                                   (59.91                                       5.33                                           6.91)    __________________________________________________________________________

                                      TABLE 67    __________________________________________________________________________    Compd.                   m.p.         Elemental Analysis (Found)    No. R.sup.1              R.sup.2        (°C.)                                  Formula C   H   N    __________________________________________________________________________    22  CH.sub.2 C(CH.sub.3).sub.3               ##STR213##    198-199                                  C.sub.31 H.sub.35 Cl.sub.2 N.sub.3 O.sub.3                                          65.49 (65.91                                              6.20 6.50                                                  7.39 7.28)    23  CH.sub.2 C(CH.sub.3).sub.3               ##STR214##    132-133                                  C.sub.32 H.sub.34 Cl.sub.2 FN.sub.3                                          64.21 (64.45                                              5.73 5.83)                                                  7.02 7.13)    24  CH.sub.2 C(CH.sub.3).sub.3               ##STR215##    118-121                                  C.sub.27 H.sub.35 Cl.sub.2 N.sub.3 O.sub.3                                  (COOH).sub.2.1/2H.sub.2 O                                          56.22 (56.37                                              6.18 6.35                                                  6.78 6.56)    25  CH.sub.2 C(CH.sub.3).sub.3               ##STR216##    179-180                                  C.sub.28 H.sub.35 Cl.sub.2 N.sub.3 O.sub.3.                                  /4H.sub.2 O                                          62.62 (62.66                                              6.66 6.54                                                  7.83 7.85)    __________________________________________________________________________

Example 92 Ethyl ester of7-chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

(1) 4-chloro-2- α-hydroxy-α-methyl-(2-chlorophenyl)methyl!aniline

A tetrahydrofuran solution of a Grignard reagent synthesized from 0.45 gof magnesium and 1.2 g of methyl iodide was added dropwise to a solutionof 2.0 g of 2-amino-5-chloro-2'-chlorobenzophenone in 20 ml oftetrahydrofuran. After refluxing with heating for 10 minutes, themixture was cooled with water, and a saturated aqueous solution ofammonium chloride was added, and the mixture was extracted with ethylacetate. The solvent was distilled off, and the residue was subjected tosilica gel column chromatography to yield 1.5 g of an oily compound.

¹ H-NMR (CDCl₃) δ: 2.04 (3H, s, CH₃), 7.0-7.8 (7H, m)

(2)N-isobutyl-4-chloro-2-(α-hydroxy-α-methyl-(2-chlorophenyl)methyl!aniline

To a solution of 1.2 g of 4-chloro-2-α-hydroxy-α-methyl-(2-chlorophenyl)methyl!aniline and 0.32 g ofisobutylaldehyde in 8 ml of acetic acid, 0.25 g of sodium borohydridewas added, followed by stirring at room temperature for 40 minutes.After water was added, the reaction mixture was extracted with ethylacetate, after which the solvent was removed and the residue wassubjected to silica gel column chromatography to yield 1.4 g of an oilycompound

¹ H-NMR (CDCl₃) δ: 0.75, 0.80 (6H, each, d, CH₃), 1.67 (1H, m), 1.99(3H, s, CH₃), 2.74 (2H, d), 7.05-7.8 (7H, m)

(3) Ethyl ester of 3- N- 4-chloro-2-α-hydroxy-α-methyl-(2-chlorophenylmethyl)phenyl!-N-isobutylcarbamoyl!acrylicacid

1.4 g of N-isobutyl-4-chloro-2-α-hydroxy-α-methyl-(2-chlorophenyl)methyl!aniline was dissolved in 15 mlof dichloromethane, and 0.7 g of sodium hydrogen carbonate was added,after which a solution of 0.68 g of monomethyl ester of chlorofumaricacid in 4 ml of dichloromethane was added dropwise over a period of 20minutes. After the mixture was washed with water and dried, the solventwas removed and the residue was subjected to silica gel columnchromatography to yield 0.65 g of a crystal.

Melting point: 153°-154° C.

Elemental analysis (for C₂₄ H₂₇ Cl₂ NO₄) Calcd.: C 62.07; H 5.86; N 3.02Found: C 62.19; H 5.86; N 2.90

(4) Ethyl ester of7-chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

1.0 g of ethyl ester of 3- N- 4-chloro-2-α-hydroxy-α-methyl-(2-chlorophenylmethyl)phenyl!-N-isobutylcarbamoyl!acrylicacid was dissolved in 10 ml of ethanol, and 0.35 g of potassiumcarbonate was added, followed by stirring for 12 hours. After water wasadded, the reaction mixture was extracted with ethyl acetate and dried,after which the solvent was removed and the residue was subjected tosilica gel column chromatography to yield 0.8 g of a crystal.

Melting point: 119°-120° C.

Elemental analysis (for C₂₄ H₂₇ Cl₂ NO₄) Calcd.: C 62.07; H 5.86; N 3.02Found: C 62.08; H 5.93; N 2.98

Example 937-chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

0.3 g of ethyl ester of7-chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid was dissolved in 10 ml of methanol, and 2 ml of a 10% aqueoussolution of potassium carbonate was added, followed by stirring for 40minutes with heating at 70° C. After acidification with dilutehydrochloric acid, the reaction mixture was extracted with ethylacetate. After the extract was dried, the solvent was removed and theresidue was recrystallized from ethyl acetate-hexane to yield 0.16 g ofa crystal.

Melting point: 153°-154° C.

Elemental analysis (for C₂₂ H₂₃ Cl₂ NO₄) Calcd.: C 60.56; H 5.31; N 3.21Found: C 60.59; H 5.32; N 2.92

Reference Example 9 Ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

(1) 5-chloro-α-(2-chlorophenyl)-2-(trifluoroacetylamino)benzyl alcohol

To a solution of 1.0 g of 2-amino-5-chloro-α-(2-chlorophenyl)benzylalcohol in 12 ml of dichloromethane, a solution of 0.8 g of anhydroustrifluoroacetic acid in 2 ml of dichloromethane was added. Afterreaction, an aqueous solution of sodium hydrogen carbonate was added,and the organic layer was dried, after which the solvent was removed andthe residue was recrystallized from hexane to yield 1.3 g of a crystal.

(2) 5-chloro-α-(2-chlorophenyl)-2-(2,2,2-trifluoroethylamino)benzylalcohol

To a suspension of 0.25 g of lithium aluminum hydride in 20 ml ofabsolute ethyl ether, a solution of 1.2 g of5-chloro-α-(2-chlorophenyl)-2-(trifluoroacetylamino)benzyl alcohol in 5ml of tetrahydrofuran was added dropwise. After mixture stirring at roomtemperature for 1 hour, water was added, and the organic layer wasdried, after which the solvent was removed and the residue was subjectedto silica gel column chromatography to yield 1.0 g of an oily compound.

(3) Ethyl ester of 3- N-4-chloro-2-(α-hydroxy-2-chlorophenylmethyl)phenyl!-N-(2,2,2-trifluoroethyl)carbamoyl!acrylicacid

5-chloro-α-(2-chlorophenyl)-2-(2,2,2-trifluoroethylamino)benzyl alcoholand monomethyl ester of chlorofumaric acid were subjected to the sameprocedure as in Reference Example 1 to yield an oily compound.

(4) Ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

Ethyl ester of 3- N-4-chloro-2-(α-hydroxy-2-chlorophenylmethyl)phenyl!-N-(2,2,2-trifluoroethyl)carbamoyl!acrylicacid was subjected to the same procedure as in Reference Example 2 toyield a crystal.

Melting point: 163°-164° C.

Elemental analysis (for C₂₁ H₁₈ Cl₂ F₃ NO₄) Calcd.: C 52.96; H 3.81; N2.94 Found: C 52.93; H 3.88; N 2.91

Reference Example 10

By the same procedure as in Reference Examples 2 and 9, the compoundslisted in Table 68 were synthesized.

                                      TABLE 68    __________________________________________________________________________     ##STR217##    Compd.     m.p.             Elemental Analysis (Found)    No. R      (°C.)                    Formula     C     H     N    __________________________________________________________________________    1   CH.sub.2 CF.sub.2 CF.sub.3               oil  .sup.1 H-NMR(CDCl.sub.3)δ: 1.25(3H, t), 2.8,                    3.1(2H, dd), 4.0-4.3(3H, m), 4.48(1H, dd), 5.1-5.35(1H,                    m), 6.18(1H, s), 6.56(1H, d), 7.2-7.8 (6H, m)         ##STR218##               106-107                    C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                                61.62 (61.66                                      5.17 5.31                                            3.12 3.16)    __________________________________________________________________________

Example 94

By the same procedure as in Reference Examples 2 and 9, the compoundslisted in Table 69 were synthesized.

                                      TABLE 69    __________________________________________________________________________     ##STR219##    Compd.      m.p.      Elemental Analysis (Found)    No. R       (°C.)                   Formula                          C      H      N    __________________________________________________________________________    1   CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3                oil                   .sup.1 H-NMR(CDCl.sub.3)δ: 0.94(9H, s), 1.25(3H, t),                   1.3-1.8(2H, m), 2.8,                   3.08(2H, dd), 3.54(1H, dt), 4.13(2H, dq), 4.35-4.6(2H,                   m),                   6.0(1H, s), 6.52(1H, d), 7.1-7.8(6H, m)    __________________________________________________________________________

Reference Example 11

The compounds obtained in Reference Examples 9 and 10 were subjected tothe same procedure as in Reference Example 4 to yield the compoundslisted in Table 70.

                                      TABLE 70    __________________________________________________________________________     ##STR220##    Compd.    m.p.         Elemental Analysis (Found)    No. R     (°C.)                   Formula C    H   N    __________________________________________________________________________    1   CH.sub.2 CF.sub.2 CF.sub.3              186-187                   C.sub.20 H.sub.14 Cl.sub.2 F.sub.5 NO.sub.4                           48.21                                2.83                                    2.81                           (47.91                                2.82                                    2.95)         ##STR221##              230-232                   C.sub.21 H.sub.19 Cl.sub.2 NO.sub.4                           60.01 (59.74                                4.56 4.55                                    3.33 3.29)    3   CH.sub.2 CF.sub.3              213-215                   C.sub.19 H.sub.14 Cl.sub.2 F.sub.3 NO.sub.4                           50.91                                3.15                                    3.12                           (50.97                                3.26                                    3.05)    __________________________________________________________________________

Example 95

The compounds obtained in Example 94 were subjected to the sameprocedure as in Reference Example 4 to yield the compounds listed inTable 71.

                                      TABLE 71    __________________________________________________________________________     ##STR222##    Compd.      m.p.         Elemental Analysis (Found)    No. R       (°C.)                     Formula C   H   N    __________________________________________________________________________    1   CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3                176-177                     C.sub.23 H.sub.26 Cl.sub.2 NO.sub.4                             61.34                                 5.60                                     3.11                             (61.45                                 5.68                                     3.25)    __________________________________________________________________________

Also, physicochemical properties of intermediates of compounds obtainedin Reference Examples 9 and 10 and Example 94 are shown in Tables 72 and73.

                                      TABLE 72    __________________________________________________________________________     ##STR223##            m.p.       Elemental Analysis (Found)    R       (°C.)               Formula C      H      N    __________________________________________________________________________    CH.sub.2 CF.sub.2 CF.sub.3            oil               C.sub.16 H.sub.12 Cl.sub.2 F.sub.6 NO                       .sup.1 HNMR(CDCl.sub.3)δ: 3.82(2H, dt), 6.17(1H,                       s),                       6.69(1H, d) 6.84(1H, d), 7.1-7.5(5H, m)     ##STR224##            oil               C.sub.17 H.sub.17 Cl.sub.2 NO                       .sup.1 HNMR(CDCl.sub.3)δ: 0.1-0.6(4H, m),                       1.0-1.2 (1H, m), 2.92(2H, d), 6.16(1H, s), 6.57(1H,                       d), 6.91(1H, d), 7.1-7.6(5H, m)    CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3            oil               C.sub.19 H.sub.23 Cl.sub.2 NO                       .sup.1 HNMR(CDCl.sub.3)δ: 0.94(9H, s),                       1.4-1.6(2H,                       m)3.1(2H, m) 6.10(1H, s), 6.62(1H, d),                       6.83(1H, d), 7.1-7.5(5H, m)    CH.sub.2 CF.sub.3            oil               C.sub.15 H.sub.12 Cl.sub.2 F.sub.3 NO                       .sup.1 HNMR(CDCl.sub.3)δ: 2.68((2H, d), 5.23(1H,                       m),                       6.15(1H, d) 6.7(1H, d), 6.83(1H, d), 7.1-7.6                       (5H, m)    __________________________________________________________________________

                                      TABLE 73    __________________________________________________________________________     ##STR225##                 m.p.       Elemental Analysis (Found)    R        R   (°C.)                    Formula C      H      N    __________________________________________________________________________    CH.sub.2 CF.sub.2 CF.sub.3             C.sub.2 H.sub.5                 oil                    C.sub.22 H.sub.18 Cl.sub.2 F.sub.6 NO.sub.4                            .sup.1 HNMR(CDCl.sub.3)δ: 1.15-1.4(3H, m),                            3.2-5.45                            (4H, m), 6.07-7.6(10H, m)     ##STR226##             C.sub.2 H.sub.5                 oil                    C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                            .sup.1 HNMR(CDCl.sub.3)δ: 0.1-0.55(4H, m),                            0.9-1.4 (4H, m), 2.4-4.4(4H, m), 6.0-7.7(10H, m)    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.3             C.sub.2 H.sub.5                 oil                    C.sub.25 H.sub.30 Cl.sub.2 NO.sub.4                            .sup.1 HNMR(CDCl.sub.3)δ: 0.76, 0.91(9H,                            both s),                            1.1-1.8(2H, m) 2.6-4.5(4H, m), 5.95-7.7                            (10H, m)    CH.sub.2 CF.sub.3             C.sub.2 H.sub.5                 oil                    C.sub.21 H.sub.18 Cl.sub.2 F.sub.3 NO.sub.4                            .sup.1 HNMR(CDCl.sub.3)δ: 1.17-1.4(3H, m),                            3.2-5.3                            (4H, m), 6.0-7.6(10H, m)    __________________________________________________________________________

Example 96 Ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-propionicacid.

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine

0.3 g of7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepineand 0.1 g of sodium cyanide were suspended in 6 ml of dimethylsulfoxide,followed by stirring at 100° C. for 1 hour. Water was added and thesuspension was extracted with ethyl acetate, after which the solvent wasremoval and the residue was subjected to silica gel columnchromatography to yield 0.25 g of a crystal.

Melting point: 194°-195° C.

Elemental analysis (for C₂₃ H₂₄ Cl₂ N₂ O₂) Calcd.: C 64.04; H 5.61; N6.49 Found: C 63.96; H 5.56; N 6.66

(2) Ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-propionicacid

To 0.2 g oftrans-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine,6 ml of an ethanol solution of 6N hydrogen chloride was added, followedby refluxing with heating for 6 hours. After solvent removal, ethylacetate and water were added, the organic layer was dried, the solventwas removed, and the residue was subjected to silica gel columnchromatography to yield 0.18 g of a crystal.

Melting point: 130°-131° C.

Elemental analysis (for C₂₅ H₂₉ Cl₂ NO₄) Calcd.: C 62.76; H 6.11; N 2.93Found: C 62.78; H 6.12; N 2.68

Example 97Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-propionicacid

90 mg of ethyl ester oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-propionicacid as obtained in Example 96 was subjected to the same procedure as inReference Example 4 to yield 80 mg of a crystal.

Melting point: 225°-227° C.

Elemental analysis (for C₂₃ H₂₅ Cl₂ NO₄) Calcd.: C 61.34; H 5.60; N 3.11Found: C 61.34; H 5.65; N 2.89

Example 98Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-ethanolTrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 was subjected to the same procedure as inExample 65 to yield 1.5 g of a crystal. Example 99 Ethyl ester of 3-trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylethyl!thioglycolicacid

(1)Trans-7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine

1.0 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-ethanolas obtained in Example 98 was dissolved in 25 ml of toluene, and 0.1 mlof pyridine and 0.4 ml of thionyl chloride were added, followed bystirring for 30 minutes with heating at 100° C. After solvent removalunder reduced pressure, the residue was dissolved in ethyl acetate andwashed with a saturated aqueous solution of sodium hydrogen carbonateand dried, after which the solvent was removed and the residue wassubjected to silica gel column chromatography to yield 0.8 g of acrystal.

Melting point: 138°-140° C.

Elemental analysis (for C₂₁ H₂₂ Cl₃ NO₂) Calcd.: C 59.10; H 5.20; N 3.28Found: C 59.17; H 5.22; N 2.25

(2) Ethyl ester of 3-trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylethyl!thioglycolicacid

0.15 g oftrans-7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine,0.08 g of ethyl ester of thioglycolic acid and 0.1 g of cesium fluoridewere added to 5 ml of acetonitrile, followed by refluxing with heatingfor 40 minutes. After ice water was added and the mixture was extractedwith ethyl acetate, the organic layer was dried, after which the solventwas removed and the residue was subjected to silica gel columnchromatography to yield 0.17 g of an oily compounds.

¹ H-NMR (CDCl₃) δ: 0.93, 1.03 (6H, each, d), 1.26 (3H, t), 1.8-2.4 (3H,m), 2.8 (2H, m), 3.19 (2H, s), 3.42 (1H, dd), 4.0-4.4 (4H, m), 6.12 (1H,s), 6.51 (1H, d), 7.2-7.8 (6H, m)

Example 100 3-trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylethyl!thioglycolicacid

0.17 g of ethyl ester of 3-trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylethyl!thioglycolicacid as obtained in Example 99 was subjected to the same procedure as inExample 51 to yield 0.18 g of a crystal.

Melting point: 194°-195° C.

Elemental analysis (for C₂₃ H₂₅ Cl₂ NO₄ S) Calcd.: C 57.26; H 5.22; N2.90 Found: C 57.27; H 5.20; N 2.96

Example 101 3-trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylethyl!sulfonylaceticacid

0.18 g of ethyl ester of 3-trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ylethyl!thioglycolicacid as obtained in Example 99 was dissolved in 8 ml of dichloromethane,and 0.25 g of m-chloroperbenzoic acid was added, followed by stirringfor 1 hour. To the reaction mixture was added an aqueous solution ofsodium hydrogen carbonate, followed by washing and the organic layer wasdried and the solvent was removed, after which the residue was subjectedto silica gel column chromatography to yield 0.18 g of an oily compound,which was then subjected to the same procedure of ethyl ester hydrolysisas in Example 51 to yield 0.13 g of a crystal.

Melting point: 171°-172° C.

Elemental analysis (for C₂₃ H₂₅ Cl₂ NO₆ S) Calcd.: C 53.70; H 4.90; N2.72 Found: C 53.62; H 4.95; N 2.68

Example 102 Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-3-(tetrazol-5-yl)phenylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-(3-cyanophenylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

To a solution of 0.5 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 and 0.15 g of m-cyanoaniline in 10 ml ofdichloromethane, 0.35 g of 1-ethyl-3-(dimethylaminopropyl)carbodiimidehydrochloride and 20 mg of dimethylaminopyridine were added, followed bystirring at room temperature for 4 hours. The solution was concentrated,and the residue was dissolved in ethyl acetate, followed by washing withwater, after which the solvent was removed and the residue was subjectedto silica gel column chromatography to yield 0.48 g of a crystal.

Melting point: 213°-214° C.

Elemental analysis (for C₂₉ H₂₇ Cl₂ N₃ O₃) Calcd.: C 64.93; H 5.07; N7.83 Found: C 64.68; H 4.96; N 7.90

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-3-(tetrazol-5-yl)phenylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

A solution of 0.2 g oftrans-7-chloro-5-(2-chlorophenyl)-3-(3-cyanophenylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepineand 80 mg of sodium azide in 5 ml of dimethylformamide was stirred at90° C. for 60 hours. After water was added, the mixture was washed withwater, after which the solvent was removed and the residue was subjectedto silica gel column-chromatography to yield 0.11 g of a crystal.

Melting point: 218°-220° C.

Elemental analysis (for C₂₉ H₂₈ Cl₂ N₆ O₃) Calcd.: C 59.64; H 4.92; N14.39 Found: C 59.44; H 4.87; N 14.30

Example 103 Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-4-(tetrazol-5-yl)phenylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine.The title compound was synthesized by the same procedure as in Example102

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-(4-cyanophenylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Melting point: 257°-259° C.

Elemental analysis (for C₂₉ H₂₇ Cl₂ N₃ O₃.1/4H₂ O) Calcd.: C 64.39; H5.12; N 7.77 Found: C 64.33; H 5.13; N 7.64

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-4-(tetrazol-5-yl)phenylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Melting point: 206°-210° C.

Elemental analysis (for C₂₉ H₂₈ Cl₂ N₆ O₃.1/4H₂ O) Calcd.: C 59.64; H4.92; N 14.39 Found: C 59.71; H 4.96; N 14.34

Example 104 Trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylaminocarbonylmethyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

0.3 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Reference Example 5 and 0.1 g of aminoacetonitrilesulfuric acid salt were dissolved in 5 ml of dimethylformaldehyde, and0.18 g of diethyl phosphorocyanidate and 0.17 ml of triethylamine wereadded, followed by stirring at room temperature for 1 hour. After waterwas added, the mixture was extracted with ethyl acetate, washed withwater and then dried. After solvent removal, the residue was subjectedto silica gel column chromatography to yield 0.31 g of a crystal.

Melting point: 216°-217° C.

Elemental analysis (for C₂₂ H₂₁ Cl₂ N₃ O₃) Calcd.: C 59.20; H 4.74; N9.41 Found: C 58.92; H 4.68; N 9.12

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Trans-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylaminocarbonylmethyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepineand sodium azide were subjected to the same procedure as in Example 102to yield a crystal.

Melting point: 253°-254° C.

Elemental analysis (for C₂₂ H₂₂ Cl₂ N₆ O₃) Calcd.: C 54.00; H 4.53; N17.17 Found: C 53.85; H 4.68; N 17.02

Example 105 Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as obtained in Example 2 was subjected to the same procedure as inExamples 102 and 104 to yield a crystalline compound.

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylaminocarbonylmethyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Melting point: 168°-169° C.

Elemental analysis (for C₂₃ H₂₃ Cl₂ N₃ O₃) Calcd.: C 60.01; H 5.04; N9.13 Found: C 60.11; H 5.28; N 9.15

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Melting point: 234°-235° C.

Elemental analysis (for C₂₃ H₂₄ Cl₂ N₆ O₃) Calcd.: C 54.88; H 4.81; N16.69 Found: C 55.07; H 4.84; N 16.92

Example 106 Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-(tetrazol-5-yl)methyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-cyanomethyl-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

0.5 g ofTrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamideas obtained in Example 91, 0.38 g of carbonyldiimidazole and 1.14 g ofallyl bromide were dissolved in 10 ml of acetonitrile, followed byrefluxing with heating for 4 hours. The solution was concentrated andethyl acetate was added, followed by washing with water, after which thesolvent was removed and the residue was subjected to silica gel columnchromatography to yield 0.44 g of a crystal.

Melting point: 158°-159° C.

Elemental analysis (for C₂₁ H₂₀ Cl₂ N₂ O₂) Calcd.: C 62.54; H 5.00; N6.95 Found: C 62.68; H 5.13; N 7.22

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-tetrazol-5-yl)methyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

0.2 g oftrans-7-chloro-5-(2-chlorophenyl)-3-cyanomethyl-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepinewas subjected to the same procedure as in Example 102 and to yield 90 mgof a crystal.

Melting point: 202°-203° C.

Elemental analysis (for C₂₁ H_(2l) Cl₂ N₅ O₂) Calcd.: C 56.51; H 4.74; N15.69 Found: C 56.29; H 4.70; N 15.67

Example 107 Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-2-(tetrazol-5-yl)ethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

(1)Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-(2-cyanoethyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

0.5 g oftrans-7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepineas obtained in Example 99 and 0.4 g of sodium cyanide were added to 8 mlof dimethylsulfoxide, followed by stirring at 100° C. for 40 minutes.After water was added, the reaction mixture was extracted with ethylacetate, and the organic layer was washed with water and dried, afterwhich the solvent was removed and the residue was subjected to silicagel column chromatography to yield 0.45 g of an oily substance.

¹ H-NMR (CDCl₃) δ: 0.93, 1.03 (6H, each, d), 1.85-2.4 (3H, m), 2.59 (2H,t), 3.43 (1H, dd), 4.05 (1H, dd), 4.33 (1H, dd), 6.14 (1H, s), 6.53 (1H,d), 7.3-7.8 (6H, m).

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-2-(tetrazol-5-yl)ethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

Trans-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepinewas subjected to the same procedure as in Example 102 to yield 0.22 g ofa crystal.

Melting point: 125°-127° C.

Elemental analysis (for C₂₂ H₂₃ Cl₂ N₅ O₂) Calcd.: C 57.40; H 5.04; N15.21 Found: C 57.15; H 5.26; N 14.97

Example 108 Trans-7-chloro-5-(2-chlorophenyl)-3-2-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)ethyl!-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

0.25 g oftrans-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepineas obtained in Example 107, 120 mg of hydroxylamine hydrochloride and0.23 g of sodium carbonate were added to 5 ml of ethanol, followed byrefluxing with heating for 18 hours. After solvent removal, ethylacetate was added, and the mixture was washed with water an dried, afterwhich the solvent was removed and the residue was recrystallized fromethyl acetate.

Melting point: 212°-214° C.

Elemental analysis (for C₂₂ H₂₅ Cl₂ N₃ O₃) Calcd.: C 58.67; H 5.60; N9.33 Found: C 58.84; H 5.68; N 9.24

0.1 g of this amidoxime, 0.1 g of carbonyldiimidazole and 0.05 ml oftriethylamine were added to 5 ml of ethyl acetate, followed by refluxingwith heating for 24 hours. The solution was concentrated and the residuewas dissolved in ethyl acetate, washed with water and dried, after whichthe solvent was removed and the residue was recrystallized from ethylacetate to yield 85 mg of a crystal.

Melting point: 241°-242° C.

Elemental analysis (for C₂₂ H₂₃ Cl₂ N₃ O₄) Calcd.: C 57.99; H 4.87; N8.82 Found: C 57.79; H 5.07; N 9.00

Example 109

Tert-butyl ester of N-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine;and tert-butyl ester of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine

In 20 ml of N,N-dimethylformamide were dissolved 0.5 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 2, and 0.26 g of L-alanine tert-butyl esterhydrochloride; under ice-cooling, to this solution were added 0.26 g ofdiethyl phosphorocyanidate and 0.41 ml of triethylamine. After stirringfor 30 minutes at room temperature, extraction was conducted with theaddition of 100 ml of water and 150 ml of ethyl acetate. The ethylacetate layer was washed with 5% aqueous solutions of potassium hydrogensulfate and sodium bicarbonate, and after drying over anhydrousmagnesium sulfate, it was distilled off under reduced pressure. Theresidue was then purified by silica gel column chromatography (eluent,hexane:ethyl acetate=2:1) to obtain, as the first fraction, 0.17 g oftert-butyl ester of N-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanineas plate crystals, m.p. 146° to 147° C.

Elemental Analysis for C₂₈ H₃₄ Cl₂ N₂ O₅ : Calcd.: C 61.20; H 6.24; N5.10 Found: C 61.20; H 6.33; N 5.15

Also, as the second fraction, 0.22 g of tert-butyl ester of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninewas obtained as an oily product.

IRν_(max) ^(neat) cm⁻¹ : 3330 (NH); 1730, 1670 (C═O)

¹ H-NMR (200 MHz, CDCl₃) δ: 0.93 (3H, d, J=6.8 Hz), 1.03 (3H, d, J =6.8Hz), 1.34 (3H, t, J=7.0 Hz), 1.46 (9H, s, Bu^(t)), 1.85-2.1 (1H, m),2.71 (1H, dd, J=14.6, 6.2 Hz), 2.89 (1H dd, J=14.6, 7.2 Hz), 3.43 (1H,dd, J=14.0, 5.4 Hz), 4.25-4.55 (3H, m), 6.13 (1H, s), 6.31 (1H, brd,NH), 6.51 (1H, d, J=2.2 Hz), 7.2-7.85 (6H, m)

Example 110 N-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine

In 10 ml of a 4N solution of hydrochloric acid in dioxane was dissolved0.16 g of tert-butyl ester of N-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine,as obtained in Example 109, and the solution was stirred overnight atroom temperature. After distillation under reduced pressure, it wascrystallized with hexane-diethylether to form 0.12 g of N-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanineas a powdery product.

Elemental Analysis for C₂₄ H₂₆ Cl₂ N₂ O₅ : Calcd.: C 58.43; H 5.31; N5.68 Found: C 58.43; H 5.65; N 5.54

¹ H-NMR spectrum (200 MHz, d₆ -DMSO) δ: 0.89 (3H, d, J=6.8 Hz), 0.94(3H, d, J=6.6 Hz), 1.25 (3H, d, J=7.2 Hz), 1.7-1.9 (1H, m), 2.4-2.55(2H, m), 3.58 (1H, dd, J=14.0, 5.0 Hz), 4.1-4.4 (3H, m), 5.99 (1H, s),6.30 (1H, d, J=2.4 Hz), 7.45-7.8 (4H, m), 8.33 (1H, d, J=7.6 Hz), 12.53(1H, br, NH)

Example 111 N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine

In 10 ml of a 4N solution of hydrochloric acid in dioxane was dissolved0.2 g of tert-butyl ester of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine,as obtained in Example 109, and the mixture was stirred for 4 hours atroom temperature. After distillation under reduced pressure, it wascrystallized from hexane-diethylether to form 0.17 g of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanineas plate crystals, m.p. 120° to 124° C.

Elemental Analysis for C₂₄ H₂₆ Cl₂ N₂ O₅.1/2H₂ O: Calcd.: C 57.37; H5.42; N 5.57 Found: C 57.37; H 5.69; N 5.48

Example 112 Methyl ester of (R)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid; and methyl ester of (R)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid.

In 50 ml of methylene chloride were dissolved 2.0 g oftrans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 2, and 0.59 g of methyl ester of (R)-lacticacid; to this solution were added 1.09 g of1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 0.2 gof 4-dimethylaminopyridine; the mixture was stirred for 1.5 hours atroom temperature. The reaction mixture was washed with 1N aqueoussolutions of hydrochloric acid and sodium bicarbonate, and after dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was separated and purified by means ofsilica gel column chromatography (eluent, hexane:diethyl ether=3:1) toyield, as the first fraction, 0.46 g of methyl ester of (R)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid as an oily product.

IRν_(max) ^(neat) cm⁻¹ : 1740, 1675 (C═O)

¹ H-NMR (200 MHz, CDCl₃) δ: 0.93 (3H, d, J=6.8 Hz), 1.02 (3H, d, J=6.6Hz), 1.49 (3H, d, J=7.2 Hz), 1.85-2.1 (1H, m), 2.91 (1H, dd, J=17.0, 5.4Hz), 3.19 (1H, dd, J=17.0, 8.0 Hz), 3.44 (1H, dd, J=13.8, 5.4 Hz), 3.72(3H, s), 4.31 (1H, dd, J=13.8, 8.4 Hz), 4.44 (1H, dd, J=8.0, 5.4 Hz),5.07 (1H, q, J =7.2 Hz), 6.14 (1H, s), 6.52 (1H, d, J=2.2 Hz), 7.2-7.8(6H, m)

As the second fraction, 0.63 g of methyl ester of (R)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid was obtained as an oily product.

IRν_(max) ^(neat) cm⁻¹ : 1740,1675 (C═O)

¹ H-NMR (200 MHz, CDCl₃) δ: 0.93 (3H, d, J=6.8 Hz), 1.03 (3H, d, J=6.6Hz), 1.48 (3H, d, J=7.0 Hz), 1.85-2.1 (1H, m), 2.93 (1H, dd, J=16.8, 7.2Hz), 3.10 (1H, dd, J=16.8, 6.2 Hz), 3.43 (1H, dd, J=13.8, 5.4 Hz), 3.28(3H, s), 4.34 (1H, dd, J=13.8, 5.4 Hz), 4.45 (1H, t, J=6.6 Hz), 5.12(1H, q, J=7.0 Hz), 6.16 (1H, s) 6.52 (1H, d, J=2.2 Hz), 7.2-7.8 (6H, m)

Example 113(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 20 ml of methanol was dissolved 0.45 g of methyl ester of (R)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid, as obtained in Example 112, to which was added 10 ml of an aqueoussolution containing 0.37 g of potassium carbonate; this mixture wasstirred for 40 minutes at 60° C. The mixture was concentrated underreduced pressure, and the concentrate subjected to extraction with theaddition of 50 ml of 1N hydrochloric acid and 100 ml of ethyl acetate.The ethyl acetate layer was washed with water, dried over anhydrousmagnesium sulfate, and distilled off under reduced pressure. The residuewas purified by means of silica gel column chromatography (eluent,hexane:ethyl acetate=3:1; eluent, hexane:methylene chloride:ethanol=5:5:1) to yield 53 mg of (3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 183° to 186° C.

α!D²⁰ +223.7° (c=0.47, methanol)

Elemental Analysis for C₂₁ H₂₁ Cl₂ NO₄ : Calcd.: C 59.73; H 5.01; N 3.32Found: C 59.36; H 5.09; N 3.19

Example 114(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro4,1-benzoxazepine-3-aceticacid

In 20 ml of methanol was dissolved 0.6 g of methyl ester of (R)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid, as obtained in Example 112, to which was added 10 ml of an aqueoussolution containing 0.49 g of potassium carbonate; this mixture wasstirred for 40 minutes at 60° C. The mixture was concentrated underreduced pressure, and the concentrate subjected to extraction with theaddition of 50 ml of 1N hydrochloric acid and 100 ml of ethyl acetate.The ethyl acetate layer was washed with water, dried over anhydrousmagnesium sulfate, and distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (eluent, hexane:ethylacetate=3:1; eluent, hexane:methylene chloride:ethanol=5:5:1) to yield54 mg of(3R,5S)-7-chloro-5-(2chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 182° to 185° C.

α!D²⁰ -215.3° (c=0.43, methanol)

Elemental Analysis for C₂₁ H₂₁ Cl₂ NO₄.1/4H₂ O: Calcd.: C 59.10; H 5.08;N 3.28 Found: C 59.05; H 5.07; N 3.53

Example 115 Methyl ester of(R)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoazepine-3-acetyl!lacticacid; and methyl ester of (R)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!acticacid

In 50 ml of methylene chloride were dissolved 2.0 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 2, and 0.57 g of methyl ester of (R)-lacticacid. To the solution were added 1.05 g of1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 0.2 gof 4-dimethylaminopyridine; the mixture was stirred for 3 hours at roomtemperature. The reaction mixture was washed with 1N solutions ofhydrochloric acid and sodium bicarbonate and dried over anhydrousmagnesium sulfate; then the solvent was distilled off under reducedpressure. The residue was separated and purified by silica gel columnchromatography (eluent, hexane:diethylether=3:1) to yield, as the firstfraction, 0.48 g of methyl ester of (R)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid as prism crystals, m.p. 155° to 157° C.

α!D²⁰ +222.6° (c=1.0, methanol)

Elemental Analysis for C₂₆ H₂₉ Cl₂ NO₆ : Calcd.: C 59.78; H 5.60; N 2.68Found: C 59.87; H 5.75; N 2.41

As the second fraction, 0.6 g of methyl ester of (R)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid was recovered as an oily product.

IRν_(max) ^(neat) cm⁻¹ : 1745, 1675 (C═O)

¹ H-NMR (200 MHz, CDCl₃) δ: 0.94 (9H, s, Bu^(t)), 1.47 (3H, d, J=7.0Hz), 2.92 (1H, dd, J=16.8, 7.2 Hz), 3.08 (1H, dd, J=16.8, 6.0 Hz), 3.39(1H, d, J =14.0 Hz), 3.72 (3H, s), 4.45 (1H, dd, J=7.2, 6.0 Hz), 4.52(1H, d, J=14.0 Hz), 5.11 (1H, q, J=7.0 Hz), 6.28 (1H, s), 6.52 (1H, s),7.3-7.8 (6H, m)

Example 116 Methyl ester of (S)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid; and methyl ester of (S)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid

In 150 ml of methylene chloride were dissolved 10 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 2, and 4.77 g of methyl ester of (S)-lacticacid. To the solution were added, under ice-cooling, 5.27 g of1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 0.3 gof 4-dimethylaminopyridine. The mixture was stirred for 2 hours at roomtemperature, followed by washing with 1N aqueous solutions ofhydrochloric acid and sodium bicarbonate, drying over magnesium sulfate.The solvent was then distilled off under reduced pressure. The residuewas separated and purified by means of silica gel column chromatography(eluent, hexane:diethylether=3:1) to yield, as the first fraction, 2.7 gof methyl ester of (S)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid as prism crystals, m.p. 155° to 157° C.

α!D²⁰ -227.1° (c=0.94, methanol)

Elemental Analysis for C₂₆ H₂₉ Cl₂ NO₆ : Calcd.: C 59.78; H 5.60; N 2.68Found: C 59.82; H 5.69; N 2.51

As the second fraction, 2.8 g of methyl ester of (S)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid was recovered as prism crystals, m.p. 119° to 120° C.

α!D²⁰ +160.1° (c=0.7, methanol)

Elemental Analysis for C₂₆ H₂₉ Cl₂ NO₆ : Calcd.: C 59.78; H 5.60; N 2.68Found: C 59.69; H 5.63; N 2.67

Example 117(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 20 ml of methanol was dissolved 0.4 g of methyl ester of (R)-O-(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid, as obtained in Example 115. To the solution was added 10 ml of anaqueous solution containing 0.32 g of potassium carbonate; the reactionmixture was then stirred for 2 hours at 60° C. and concentrated underreduced pressure, followed by extraction by the addition of 50 ml of 1Nhydrochloric acid and 50 ml of ethyl acetate. The ethyl acetate layerwas washed with water, dried over anhydrous magnesium sulfate, thendistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (eluent, hexane:ethyl acetate=2:1;methylene chloride:methanol=3:1) to yield 0.15 g of(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as needles, m.p. 241° to 245° C.

α!D²⁰ +244.8° (c=0.52, methanol)

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₄.1/4H₂ O: Calcd.: C 59.94; H 5.37;N 3.18 Found: C 60.19; H 5.47; N 2.97

Example 118(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (1); and ethyl ester of(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (2)

In 45 ml of methanol was dissolved 2.2 g of methyl ester of (S)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid, as obtained in Example 116, to which was added 15 ml of an aqueoussolution containing 1.75 g of potassium carbonate; the mixture was thenstirred for 2 hours at 60° C, concentrated under reduced pressure andsubjected to extraction with the addition of100 ml of 1N hydrochloricacid and 100 ml of ethyl acetate. The ethyl acetate layer was washedwith water, dried over anhydrous magnesium sulfate, then distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=2:1; methylenechloride:methanol=3:1) to yield crystals. Recrystallization fromhexane-ethanol yielded 0.85 g of(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as needles, m.p. 250° to 252° C.

α!D²⁰ -252.0° (c=0.5, methanol)

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₄ : Calcd.: C 59.94; H 5.37; N 3.28Found: C 59.84; H 5.28; N 3.31

The filtrate was distilled off under reduced pressure; the residue wasthen dissolved in 30 ml of ethanol, to which 0.3 ml of concentratedsulfuric acid was added; the mixture was then stirred for 2 days.Distillation under reduced pressure was followed by extraction with theaddition of 100 ml of water and 100 ml of ethyl acetate. The ethylacetate layer was washed with aqueous sodium bicarbonate and with water,dried over anhydrous magnesium sulfate, and distilled off under reducedpressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=5:1) to yield 0.63 g ofethyl ester of(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 120° to 121° C.

α!D²⁰ -235.5° (c=0.51, methanol)

Elemental Analysis for C₂₄ H₂₇ Cl₂ NO₄ : Calcd.: C 62.07; H 5.86; N 3.02Found: C 62.10; H 5.95; N 2.93

Also, in substantially the same manner as above, the hydrolysis of 0.6 gof methyl ester of (R)-O-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,-benzoxazepine-3-acetyl!lacticacid yielded 0.37 g of(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid.

Example 119 Ethyl ester of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,3-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

In 5 ml of N,N-dimethylformamide were dissolved 0.15 g of(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 118, and 58 mg of glycine ethylesterhydrochloride. To the solution were added, under ice-cooling, 71 mg ofdiethyl phosphorocyanidate and 0.12 ml of triethylamine. After thereaction mixture was stirred for 30 minutes at room temperature, it wassubjected to extraction with the addition of 50 ml of water and 50 ml ofethyl acetate. The ethyl acetate layer was washed with 1N hydrochloricacid and an aqueous solution of sodium bicarbonate, dried over anhydrousmagnesium sulfate, and distilled off under reduced pressure. The residuewas purified by means of silica gel column chromatography (eluent,hexane:ethyl acetate=1:1) to yield 0.16 g of ethyl ester of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid as plate crystals, m.p. 138° to 139° C.

α!D²⁰ -220.8° (c=0.45, methanol)

Elemental Analysis for C₂₆ H₃₀ Cl₂ N₂ O₅ : Calcd.: C 59.89; H 5.80; N5.37 Found: C 59.86; H 5.94; N 5.12

Example 120 N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

In 5 ml of ethanol was dissolved 0.12 g of ethyl ester of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid, as obtained in Example 119, to which was added 2 ml of 1N sodiumhydroxide. The reaction mixture was stirred for 15 minutes at roomtemperature, after which was subjected to extraction with the additionof 50 ml of 1N hydrochloric acid and 50 ml of ethyl acetate. The ethylacetate layer was washed with water, dried over anhydrous magnesiumsulfate, and distilled off under reduced pressure to leave 0.10 g of N-(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid as a powdery product.

α!D²⁰ -229.8° (c=0.46, methanol)

Elemental Analysis for C₂₄ H₂₆ Cl₂ N₂ O₅ : Calcd.: C 58.43; H 5.31; N5.68 Found: C 58.56; H 5.63; N 5.57

Example 121(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid; and(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In ethanol were dissolved 10 g of7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 2, and quinine of equal molarity. Afterthis mixture was concentrated, 150 ml of ethyl ether was added, andcrystallization was allowed to occur under ice-cooling. The crystalsthus obtained were dissolved in a mixture of ethanol and ethyl ether andallowed to recrystallize. The mother liquor was removed from thecrystals thus formed, and was concentrated, leaving a residue. Thisresidue underwent recrystallization using hexane, and the crystals thusformed were dissolved in ethyl acetate. The quinine in this solution wasremoved with dilute hydrochloric acid. The residue after removal of thesolvent underwent recrystallization using hexane, resulting in(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as crystals. The solvent was then removed from the mother liquorremaining from the very first crystallization. The residue was dissolvedin ethyl acetate, and the quinine was removed with dilute hydrochloricacid. The solvent was removed, leaving a residue which wasrecrystallized using a mixture solvent of ethanol and ethyl ether. Afterremoval of the crystals thus formed, the mother liquor was concentrated,and the residue recrystallized using hexane, resulting in(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as crystals.

Example 122 Ethyl ester of(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid; and ethyl ester of(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

To ethyl iodide in dimethyl formamide as a solvent, and under thepresence of potassium carbonate, were added, as separate reactions,(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid and(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 121, resulting in the above compounds.Ethyl ester of(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, m.p. 117° to 118° C.

α!D²⁰ +224.6° (c=0.5, MeOH)

Elemental Analysis for C₂₄ H₂₇ Cl₂ NO₄ : Calcd.: C 62.07; H 5.86; N 3.02Found: C 62.01; H 5.88; N 2.97

Example 123 Ethyl ester oftrans-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

(1) 2-amino-5-chloro-2'-hydroxybenzophenone

A mixture of 2.15 g of 2-amino-5-chloro-2'-methoxybenzophenone and 20 mlof 47% hydrogen bromide was heated for 1 hour under reflux. The solutionwas rendered neutral with sodium bicarbonate, and subjected toextraction with 100 ml of ethyl acetate. The extract solution was washedwith water and dried over anhydrous magnesium sulfate; the solvent wasthen distilled off under reduced pressure. The residue was purified bymeans of silica gel column chromatography (eluent, hexane:ethylacetate=10:1) to yield 1.9 g of 2-amino-5-chloro-2'-hydroxybenzophenoneas needles, m.p. 51° to 52° C.

Elemental Analysis for C₁₃ H₁₀ ClNO₂ : Calcd.: C 63.04; H 4.07; N 5.66Found: C 62.90; H 4.04; N 5.61

A mixture of 10 g of 2-acetylamino-5-chloro-2'-methoxybenzophenone and100 ml of 47% hydrogen bromide was heated for 2 hours under reflux. Thesolution was rendered neutral with sodium hydroxide, and was subjectedto extraction with 200 ml of ethyl acetate. The extract solution waswashed with water and dried over anhydrous magnesium sulfate; thesolvent was then distilled off under reduced pressure. The residue waspurified by means of silica gel column chromatography (eluent,hexane:ethyl acetate=5:1) to yield 8.0 g of2-amino-5-chloro-2'-hydroxybenzophenone as needles.

(2) 2-amino-5-chloro-2'-ethoxybenzophenone

In 10 ml of N,N-dimethylformamide was dissolved 1.5 g of2-amino-5-chloro-2'-hydroxybenzophenone, as obtained in (1), to whichwere added 1.26 g of potassium carbonate and 0.63 ml of ethyl iodide.The reaction mixture was stirred for 3 hours at room temperature, afterwhich it was subjected to extraction with 100 ml of water and 100 ml ofethyl acetate. The ethyl acetate layer was washed with water, dried overanhydrous magnesium sulfate, and distilled off under reduced pressure.The residue was purified by means of silica gel column chromatography(eluent, hexane:ethyl acetate=5:1) to yield 1.6 g of2-amino-5-chloro-2'-ethoxybenzophenone as an oily product.

IRν_(max) ^(neat) cm⁻¹ : 3460, 3340 (NH); 1610 (C═O)

¹ H-NM spectrum (200 MHz, CDCl₃) 67 : 1.21 (3H, t, J=7.0 Hz), 4.04 (2H,q, J=7.0 Hz), 6.1-6.5 (2H, br, NH₂), 6.65 (1H, d, J=8.8 Hz), 6.9-7.1(2H, m), 7.15-7.35 (3H, m), 7.35-7.5 (1H, m)

(3) 2-amino-5-chloro-α-(2-ethoxyphenyl)benzyl alcohol

In 30 ml of ethanol was dissolved 1.5 g of2-amino-5-chloro-2'-ethoxybenzophenone, as obtained in (2), to which wasadded 0.34 g of sodium borohydride. The reaction mixture was stirredovernight at room temperature. After the ethanol was distilled off underreduced pressure and after dissociation by the addition of an aqueoussolution of hydrochloric acid, 50 ml of 1N sodium hydroxide was added torender the solution neutral, and extraction was carried out with 100 mlof ethyl acetate. The ethyl acetate layer was washed with water, driedover anhydrous magnesium sulfate, and distilled off under reducedpressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=3:1) to yield 1.35 g of2-amino-5-chloro-α-(2-ethoxyphenyl)benzyl alcohol as prism crystals,m.p. 80° to 81° C.

Elemental Analysis of C₁₅ H₁₆ ClNO₂ : Calcd.: C 64.87; H 5.81; N 5.04Found: C 64.77; H 5.81; N 4.85

(4) 5-chloro-α-(2-ethoxyphenyl)-2-isobutylaminobenzyl alcohol

In 10 ml of acetic acid were dissolved 1.3 g of2-amino-5-chloro-α-(2-ethoxyphenyl)benzyl alcohol, as obtained in (3),and 0.47 ml of isobutylaldehyde, to which was added, under ice-cooling,0.24 g of sodium borohydride. The reaction mixture was stirred for 30minutes at room temperature, after which it was subjected to extractionwith the addition of 100 ml of water and 100 ml of ethyl acetate. Theethyl acetate layer was washed with 1N sodium hydroxide, dried overanhydrous magnesium sulfate, and then distilled off under reducedpressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=20:1 to 5:1) to yield 1.5 gof 5-chloro-α-(2-ethoxyphenyl-2-isobutylaminobenzyl alcohol as an oilyproduct.

IRν_(max) ^(neat) cm⁻¹ : 3520, 3410 (NH, OH)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 0.90 (3H, d, J=6.8 Hz), 0.91 (3H,d, J=6.6 Hz), 1.41 (3H, t, J=7.0 Hz), 1.7-2.0 (1H, m), 2.89 (2H, d,J=6.8 Hz), 3.2-3.6 (1H, br), 4.13 (2H, q, J=7.0 Hz), 4.7-5.1 (1H, br),5.97 (1H, s) 6.55 (1H, d, J=8.6 Hz), 6.85-7.4 (6H, m)

(5) Ethyl ester of 3- N- 4-chloro-2-2-ethoxy-α-hydroxybenzyl!phenyl!-N-isobutylcarbamoyl!acrylic acid

A solution containing 0.84 g of monoethyl ester of fumaric acid and 1.28ml of thionyl chloride in 10 ml of toluene was stirred for 30 minutes at90° C. The solvent was distilled off under reduced pressure, leavingmonoethyl ester acid chloride of fumaric acid. This product and 1.5 g of5-chloro-α-(2-methoxyphenyl)-2-isobutylaminobenzyl alcohol, as obtainedin (4), were then dissolved in 30 ml of methylene chloride, to which0.75 g of sodium bicarbonate was added; the mixture was then stirred for30 minutes at room temperature. The reaction mixture was washed withwater and dried over anhydrous magnesium sulfate; the solvent was thendistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (eluent, hexane:ethyl acetate=4:1)to yield 1.95 g of ethyl ester of 3- N- 4-chloro-2-2-ethoxy-α-hydroxybenzyl!phenyl!-N-isobutylcarbamoyl!acrylic acid as anoily product.

IRν_(max) ^(neat) cm⁻¹ : 3400 (OH); 1720, 1660, 1630 (C═C, C═O)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 0.65-1.0 (6H, m), 1.15-1.5 (6H, m),1.6-2.0 (1H, m), 2.3-3.0 (2H, m), 3.9-4.4 (5H, m), 5.8-6.3 (3H, m),6.6-8.05 (7H, m)

(6) Ethyl ester oftrans-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 30 ml of ethanol was dissolved 1.95 g of ethyl ester of 3- N-4-chloro-2- 2-ethoxy-α-hydroxybenzyl!phenyl!-N-isobutylcarbamoyl!acrylicacid, as obtained in (5), to which was added 1.17 g of potassiumcarbonate, and the mixture was stirred overnight. The reaction mixturewas subjected to extraction with 100 ml of water and 100 ml of ethylacetate. The ethyl acetate layer was washed with water, dried overanhydrous magnesium sulfate, and distilled off under reduced pressure.The residue was purified by means of silica gel column chromatography(eluent, hexane:ethyl acetate=5:1) to yield 1.55 g of ethyl ester oftrans-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 129° to 130° C.

Elemental Analysis for C₂₅ H₃₀ ClNO₅ : Calcd.: C 65.28; H 6.57; N 3.05Found: C 65.38; H 6.44; N 2.91

Example 124Trans-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 30 ml of methanol was dissolved 1.25 g of ethyl ester oftrans-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 123, to which was added 10 ml of an aqueoussolution containing 0.75 g of potassium carbonate; the mixture was thenstirred for 3 hours at 60° C. After the reaction mixture wasconcentrated under reduced pressure, it was rendered acid by theaddition of 50 ml of 1N hydrochloric acid, and subjected to extractionwith 100 ml of ethyl acetate. The extract solution was washed with waterand dried over anhydrous magnesium sulfate; the solvent was thendistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (eluent, hexane:ethyl acetate=2:1;eluent, hexane:dichloromethane:ethanol=5:5:1) to yield 0.66 g oftrans-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 190° to 192° C.

Elemental Analysis for C₂₃ H₂₆ ClNO₅ : Calcd.: C 63.96; H 6.07; N 3.24Found: C 63.64; H 5.96; N 3.58

Example 125 Ethyl ester oftrans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

(1) 2-amino-2'-benzyloxy-5-chlorobenzophenone

In 30 ml of N,N-dimethylformamide was dissolved 5.0 g of2-amino-5-chloro-2'-hydroxybenzophenone, as obtained in Example 123 (1),to which were added 4.2 g of potassium carbonate and 2.9 ml of benzylbromide; the mixture was then stirred for 2 hours at room temperature.The mixture was subjected to extraction with 150 ml of water and 200 mlof ethyl acetate, and the ethyl acetate layer was washed with water,dried over anhydrous magnesium sulfate, and distilled off under reducedpressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=10:1 to 5:1) to yield 6.4 gof 2-amino-2'-benzyloxy-5-chlorobenzophenone as prism crystals, m.p.110° to 111° C.

Elemental Analysis for C₂₀ H₁₆ ClNO₂ : Calcd.: C 71.11; H 4.77; N 4.15Found: C 71.34; H 4.80; N 4.23

(2) 2-amino-α-(2-benzyloxyphenyl)-5-chlorobenzyl alcohol

In 50 ml of methanol was dissolved 6.0 g of2-amino-2'-benzyloxy-5-chlorobenzophenone, as obtained in (1), to whichwas added 1.12 g of sodium borohydride; the mixture was then stirred for4 hours at room temperature. After ethanol was distilled off underreduced pressure, with dissociation by the addition of an aqueoussolution of hydrochloric acid, the reaction mixture was rendered neutralby the addition of 50 ml of 1N sodium hydroxide and subjected toextraction with 200 ml of ethyl acetate. The ethyl acetate layer waswashed with water, dried over anhydrous magnesium sulfate, thendistilled off under reduced pressure to leave 5.9 g of2-amino-α-(2-benzyloxyphenyl)-5-chlorobenzyl alcohol as plate crystals,m.p. 120° to 121° C.

Elemental Analysis for C₂₀ H₁₈ ClNO₂ : Calcd.: C 70.69; H 5.34; N 4.12Found: C 70.85; H 5.16; N 4.24

(3) α-(2-benzyloxyphenyl)-5-chloro-2-isobutylaminobenzyl alcohol

In 50 ml of acetic acid were dissolved 5.0 g of2-amino-α-(2-benzyloxyphenyl)-5-chlorobenzyl alcohol, as obtained in(2), and 1.47 ml of isobutylaldehyde. To the solution was added, underice-cooling, 0.74 g of sodium borohydride. The reaction mixture wasstirred for 30 minutes at room temperature, and, after addition of 150ml of water, was subjected to extraction with 200 ml of ethyl acetate.The extract solution was washed with 1N sodium hydroxide and dried overanhydrous magnesium sulfate; then the solvent was distilled off underreduced pressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=20:1 to 5:1) to yield 5.6 gof α-(2-benzyloxyphenyl)-5-chloro-2-isobutylaminobenzyl alcohol as prismcrystals, m.p. 79° to 80° C.

Elemental Analysis for C₂₄ H₂₆ ClNO₂ : Calcd.: C 72.81; H 6.62; N 3.54Found: C 72.95; H 6.62; N 3.62

(4) Ethyl ester of 3- N- 4-chloro-2-2-benzyloxy-α-hydroxybenzyl!phenyl!-N-isobutylcarbamoyl!acrylic acid

A solution comprised of 2.65 g of monoethyl ester of fumaric acid and4.0 ml of thionyl chloride in 30 ml of toluene was stirred for 1 hour at90° C. It was then distilled under reduced pressure, leaving monoethylester acid chloride of fumaric acid. This product and 5.6 g ofα-(2-benzyloxyphenyl)-5-chloro-2-isobutylaminobenzyl alcohol, asobtained in (3), were dissolved in 100 ml of methylene chloride; afterthe addition of 2.38 g of sodium bicarbonate, the mixture was stirredfor 30 minutes at room temperature. The reaction mixture was washed withwater and dried over anhydrous magnesium sulfate; then the solvent wasdistilled off under reduced pressure to yield 6.4 g ethyl ester of 3- N-4-chloro-2-2-benzyloxy-α-hydroxybenzyl!phenyl!-N-isobutylcarbamoyl!acrylic acid asprism crystals, m.p. 169° to 171° C.

Elemental Analysis for C₃₀ H₃₂ ClNO₅ : Calcd.: C 69.02; H 6.18; N 2.68Found: C 69.24; H 6.04; N 2.71

(5) Ethyl ester oftrans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 150 ml of ethanol was dissolved 6.0 g of ethyl ester of 3- N-4chloro-2-2-benzyloxy-α-hydroxybenzyl!phenyl!-N-isobutylcarbamoyl!acrylic acid, asobtained in (4), to which was added 3.18 g of potassium carbonate; themixture was then stirred overnight. The solvent was distilled off underreduced pressure, and the residue was subjected to extraction with 150ml of water and 200 ml of ethyl acetate. The ethyl acetate layer waswashed with water and dried over anhydrous magnesium sulfate, thendistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (eluent, hexane:ethyl acetate=5:1)to yield 5.8 g of ethyl ester oftrans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 146° to 147° C.

Elemental Analysis for C₃₀ H₃₂ ClNO₅ : Calcd.: C 69.02; H 6.18; N 2.68Found: C 69.20; H 6.21; N 2.95

Example 126Trans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In a mixture of 20 ml of methanol and 10 ml of tetrahydrofuran wasdissolved 0.5 g of ethyl ester oftrans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 125. To this solution was added 10 ml of anaqueous solution containing 0.66 g of potassium carbonate, and themixture was stirred for 6 hours at 60° C. The reaction mixture wasconcentrated under reduced pressure, rendered acid by the addition of 50ml of 1N hydrochloric acid, and subjected to extraction with 100 ml ofethyl acetate. The extract solution was washed with water and dried overanhydrous magnesium sulfate; then the solvent was distilled off underreduced pressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=3:1; eluent,hexane:dichloromethane:ethanol=5: 5:1) to yield 0.21 g oftrans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 194° to 197° C.

Elemental Analysis for C₂₈ H₂₈ ClNO₅ : Calcd.: C 68.08; H 5.71; N 2.84Found: C 68.07; H 5.75; N 2.85

Example 127 Ethyl ester oftrans-7-chloro-5-(2-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 50 ml of ethyl acetate was dissolved 3.5 g of ethyl ester oftrans-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 125. To this solution was added 1.0 g of10% palladium carbon and hydrogenolysis was then allowed to occur atnormal temperature and pressure. After the calculated amount of hydrogenwas absorbed, the catalyst was removed, and the ethyl acetate wasdistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (eluent, hexane:ethyl acetate=3:1)to yield 2.8 g of ethyl ester oftrans-7-chloro-5-(2-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as an oily product.

IRν_(max) ^(neat) cm⁻¹ : 3380 (OH); 1730, 1670, 1650 (C═O)

¹ H-NMR spectrum (200 NHz, CDCl₃) δ: 0.90 (3H, d, J=6.6 Hz),0.99 (3H, d,J=6.6 Hz), 1.24 (3H, t, J=7.2 Hz), 1.9-2.2 (1H, m), 2.85 (1H, dd J=17.8,5.0 Hz), 2.97 (1H, d, J=17.8, 8.2 Hz), 3.41 (1H, dd, J=13.8, 6.4 Hz),4.16 (2H, q, J=7.2 Hz), 4.30 (1H, dd, J=13.8, 7.8 Hz), 4.49 (1H, dd,J=8.2, 4.8 Hz), 5.97 (1H, s), 6.85 (1H, d, J=2.4 Hz), 6.85-7.5 (6H, m),7.54 (1H, OH)

Example 128 Trans-7-chloro-5-(2-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid

In 10 ml of methanol was dissolved 0.4 g of ethyl ester oftrans-7-chloro-5-(2-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 127, to which was added 5 ml of an aqueoussolution containing 0.51 g of potassium carbonate; the mixture was thenstirred for 1 hour at 60° C. The reaction mixture was condensed underreduced pressure, rendered acid by the addition of 50 ml of 1Nhydrochloric acid, and subjected to extraction with 100 ml of ethylacetate. The extract solution was washed with water and dried overanhydrous magnesium sulfate; the solvent was then distilled off underreduced pressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=2:1; eluent,hexane:dichloromethane:ethanol=5:5:2) to yield 0.11 g oftrans-7-chloro-5-(2-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 238° to 242° C. (decomposition).

Elemental Analysis for C₂₁ H₂₂ ClNO₅ : Calcd.: C 62.45; H 5.49; N 3.47Found: C 62.55; H 5.68; N 3.41

Example 129 Ethyl ester oftrans-7-chloro-1-isobutyl-5-(2-isopropyloxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 10 ml of N,N-dimethylformamide was dissolved 0.7 g of ethyl ester oftrans-7-chloro-5-(2-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 127, to which was added 0.34 g of potassiumcarbonate and 0.24 ml of isopropyl iodide; the mixture was then stirredovernight at room temperature. The mixture was subjected to extractionwith 100 ml of water and 150 ml of ethyl acetate, after which the ethylacetate layer was washed with 1N hydrochloric acid and sodiumbicarbonate, dried over anhydrous magnesium sulfate, and distilled offunder reduced pressure. The residue was purified by means of silica gelcolumn chromatography (eluent, hexane:ethyl acetate=3:1) to yield 0.55 gof ethyl ester oftrans-7-chloro-1-isobutyl-5-(2-isopropyloxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as needles, m.p. 135° to 137° C.

Elemental Analysis for C₂₆ H₃₂ ClNO₅ : Calcd.: C 65.88; H 6.80; N 2.96Found: C 66.09; H 6.83; N 3.24

Example 130Trans-7-chloro-1-isobutyl-5-(2-isopropyloxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 20 ml of methanol was dissolved 0.4 g of ethyl ester oftrans-7-chloro-5-(2-isopropyloxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid, as obtained in Example 129. To this solution was added 10 ml of anaqueous solution containing 0.23 g of potassium carbonate; the mixturewas then stirred for 3 hours at 80° C. The reaction mixture wasconcentrated under reduced pressure, rendered acid by the addition of 50ml of 1N hydrochloric acid, and subjected to extraction with 100 ml ofethyl acetate. The extract solution was washed with water and dried overanhydrous magnesium sulfate, the solvent was then distilled off underreduced pressure. The residue was purified by means of silica gel columnchromatography (eluent, hexane:ethyl acetate=3:1; eluent,hexane:dichloromethane:ethanol=5:5:1) to yield 0.24 g of trans-7-chloro1-isobutyl-5-(2-isopropyloxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prism crystals, m.p. 146° to 149° C.

Elemental Analysis for C₂₄ H₂₈ ClNO₅.0.2H₂ O: Calcd.: C 64.12; H 6.37; N3.11 Found: C 64.18; H 6.37; N 3.28

Example 131 Ethyltrans-7-bromo-1-neopentyl-2-oxo-5-(2-pyridyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

(1) 2-Amino-5-bromo-α-(2-pyridyl)benzyl alcohol

In 100 ml of methanol was dissolved 10 g of2-amino-5-bromophenyl-2-pyridylketone. To the solution was added 1.7 gof sodium borohydride and stirred for 30 minutes. The solvent methanolwas evaporated off under reduced pressure. The residue was treated withan aqueous solution of hyrochloric acid. The decomposed residue was thenneutralized with 200 ml of a sodium bicarbonate aqeous solution, andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=2:1) to give2-amino-5-bromo-α-(2-pyridyl)benzyl alcohol (9.0 g) as prisms, m.p.104°-105° C.

Elementary analysis for C₁₂ H₁₁ BrN₂ O Calcd.: C 51.64; H 3.97; N 10.04Found: C 51.61; H 3.93; N 10.04

(2) 5-Bromo-2-neopentylamino-α(2-pyridyl)benzyl alcohol

In 20 ml of acetic acid was dissolved 2.0 g of2-amino-5-bromo-α-(2-pyridyl)benzyl alcohol obtained in (1) togetherwith 0.86 ml of trimethylacetoaldehyde. To the solution was added 0.36 gof sodium borohydride under ice-cooling. The reaction mixture wasstirred for 30 minutes at room temperature and then subjected toextraction with a mixture of 100 ml of water and 150 ml of ethylacetate. The ethyl acetate layer was washed with 1N sodium hydroxide,dried over anhydrous magnesium sulfate, and concentrated to drynessunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent, hexane:ethyl acetate=5:1) to afford5-bromo-2-neopentylamino-α-(2-pyridyl)benzyl alcohol (2.4 g) as am oilyproduct.

IRν_(Max) ^(Neat) cm⁻¹ : 3390, 3280 (NH,OH)

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 0.80 (9H, s, But), 2.68 (2H, s),5.69 (1H, s), 6.48 (1H, d, J=8.4Hz), 7.1-7.35 (4H, m), 7.55-7.7 (1H, m),8.5-8.6 (1H, m).

(3) Ethyl 3- N- 4-bromo-2-α-(2-pyridyl)hydroxymethyl!phenyl!-N-neopentylcarbamoyl!acrylate

In 50 ml of dichloromethane was dissolved 2.4 g of5-bromo-2-neopentylamino-α-(2-pyridyl)benzyl alcohol obtained in (2). Tothe solution were added 1.15 g of sodium borohydride and 1.23 g ofmonomethyl fumarate acid chloride. After stirring for 2 hours at roomtemperature, the reaction mixture was washed with water and dried overanhydrous magnesium sulfate. The solvent was evaporated off underreduced pressure. The residue was purified by column chromatographyusing silica gel (eluent, hexane:ethyl acetate=2:1) to give ethyl 3- N-4-bromo-2- α-(2-pyridyl)hydroxymethyl!phenyl!-N-neopentylcarbamoyl!acrylate as prisms, m.p.165°-166° C.

Elementary analysis for C₂₃ H₂₇ BrN₂ O₄ : Calcd.: C 58.11; H 5.72; N5.89 Found: C 58.21; H 5.65; N 6.14

(4) Ethyltrans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

In 30 ml of ethanol was dissolved 2.0 g of ethyl 3- N- 4-bromo-2-α-(2-pyridyl) hydroxymethyl!phenyl!-N-neopentylcarbamoyl!acrylateobtained in (3). To the solution was added 1.16 g of potassium carbonateand the mixture was stirred overnight at room temperature. The solventwas evaporated off under reduced pressure. The residue was thenextracted with 100 ml of water and 100 ml of ethyl acetate. The organiclayer was washed with water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The redudue was purified on asilica gel column (eluent, hexane:ethyl acetate=3:1) to give 1.9 g ofethyltrans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate as an oily product.

IRν_(Max) ^(Neat) cm⁻¹ : 1730, 1675 (C═O)

¹ H-NMR (CDCl₃) δ: 0.94(9H,s,Bu^(t)), 1.25(3H,t,J=7.2 Hz),2.80(1H,dd,J=16.6,5.8 Hz), 3.07(1H,dd,J=16.6,7.8 Hz), 3.31 (1H,d,J=13.8Hz), 4.13(2H,q,J=7.2 Hz), '4.44(1H,dd,J=7.8,5.8 Hz), 4.49(1H,d,J=13.8Hz), 6.07 (1H,s), 6.59(1H,d,J=2.2 Hz), 7.2-7.9 (5H,m), 8.6-8.7(1H,m)

Example 132Trans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

In 20 ml of methanol was dissolved 1.9 g of ethyltrans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate obtained in Example 131. To thesolution was added 10 ml of an aqueous solution containing 1.1 g ofpotassium carbonate. The mixture was heated and refluxed for 30 minutes,and then concentrated under reduced pressure. The concentrate wascrystallized by the addition of 30 ml of a hydrochloric acid aqueoussolution. The product was collected by filteration and recrystallizedfrom hexane and ethanol to give 1.25 g oftrans-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as prisms, m.p. >263° C. (decomp.)

Elementary analysis for C₂₁ H₂₃ BrN₂ O₄ Calcd.: C 56.39; H, 5.18; N 6.26Found: C 56.39; H, 5.18; N 6.10

Example 133 Ethyl N-benzyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetate

In 10 ml of dimethylformamide were dissolved 0.3 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Example 2 and 0.27 g of N-benzylglycine ethyl ester. Tothe solution was added 0.24 g of diethyl phosphorocyanidate togetherwith 0.19 ml of triethylamine under ice-cooling. The mixture was stirredfor 30 minutes at room temperature and then subjected to extraction witha mixture of 100 ml of water and 100 ml of ethyl acetate. The ethylacetate layer was washed with 1N hydrochloric acid and with a sodiumbicarbonate aqueous solution, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent, hexane:ethyl acetate=3:1) toafford ethyl N-benzyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetate (0.56 g) as prisms, m.p. 195°-197° C.

Elementary Analysis for C₃₃ H₃₆ Cl₂ N₂ O₅ Calcd.: C 64.81; H 5.93; N,4.58 Found: C 64.84; H 5.97; N 4.45

Example 134 N-Benzyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetic acid

In 15 ml of methanol was dissolved 0.3 g of ethyl N-benzyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetate obtained in Example 133. To the solution was added 4 ml ofsodium hydroxide and the mixture was stirred for 20 minutes. Thereaction mixture, after acidified with 50 ml of 1N HCl, was subjected toextraction with 100 ml of ethyl acetate. The ethyl acetate layer waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to yield N-benzyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!amino acetic acid as prisms, m.p. 190°-192° C.

Elementary Analysis for C₃₁ H₃₂ Cl₂ N₂ O₅ : Calcd.: C 63.81; H 5.53; N4.80 Found: C 64.02; H 5.85; N 4.81

Example 135 Methyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-N-phenylaminoacetate

A mixture of 0.6 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Example 2, 10 ml of thionyl chloride and 10 ml oftoluene was stirred for 30 minutes at 90° C., and then concentratedunder reduced pressure. The concentrate trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetylchloride was dissolved in 10 ml of methylene chloride. To the solutionwere added 0.27 g of N-phenylglycine methyl ester and 0.23 ml oftriethylamine. The mixture was stirred for one hour at room temperature,and then subjected to extraction with 100 ml of ethyl acetate. Theorganic layer was washed with 1N HCl and with a sodium bicarbonateaqueous solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure.

The residue was purified on a silica gel column (eluent, hexane:ethylacetate=3:1) to give methyl N- trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-N-phenylamino acetate (0.35 g) as prisms, m.p. 226°-228° C.

Elementary Analysis for C₃₁ H₃₂ Cl₂ N₂ O₅ : Calcd.: C 63.81; H 5.53; N4.80 Found: C 63.78; H 5.59; N 4.60

Example 136 N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-N-phenylaminoacetic acid

In 3 ml of methanol was dissolved 0.25 g of methyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-N-phenylamino acetate obtained in Example 135. To the solution was added 2 ml of1N sodium hydroxide. The mixture was stirred for 1.5 hours at 60° C. andthen acidified with 50 ml of 1N HCl for extraction with ethyl acetate.The ethyl acetate layer was washed with water, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressured 6 give 0.23g of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-N-phenylaminoaceticacid 0.23 g) as prisms, m.p. 238°-240° C.

Elementary Analysis for C₃₀ H₃₀ Cl₂ N₂ O₅ : Calcd.: C 63.27; H 5.31; N4.92 Found: C 63.46; H 5.54; N 4.70

Example 137 Ethyl N- trans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!amino acetate

In 10 ml of dimethylformamide were dissolved 0.3 g oftrans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Example 74 and 0.12 g of glycine ethyl esterhydrochloride. To the solution were added 0.14 g of diethylphosphorocyanidate and 0.24 ml of triethylamine under ice-cooling. Themixture was stirred for 30 minutes at room temperature and thensubjected to extraction with 100 ml of water and 100 ml of ethylacetate. The ethyl acetate layer was washed with 1N HCl and with asodium bicarbonate aqueous solution and dried over anhydrous magnesiumsulfate. Ethyl acetate was evaporated off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent,hexane:ethyl acetate =1:1) to yield ethyl N-trans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetate (0.33 g) as needles, m.p. 233°-236° C.

Elementary Analysis for C₂₇ H₃₃ ClN₂ O₆ Calcd.: C 62.72; H 6.43; N 5.42Found: C 62.54; H 6.47; N 5.28

Example 138 N-Trans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoaceticacid

In 5 ml of ethanol was dissolved 0.25 g of ethyl N-trans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!aminoacetateobtained in Example 137. To the solution was added 2 ml of ml of 1NNaOH. After stirring for 15 minutes acidified with 100 ml of 1N HCl andsubjected to extraction with ethyl acetate. The organic layer was washedwith water and dried over anhydrous magnesium sulfate. Ethyl acetate wasevaporated off under reduced pressure to afford N-trans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- acetyl!amino acetic acid asprisms, m.p. 239°-242° C.

Elementary Analysis for C₂₅ H₂₉ ClN₂ O₅ Calcd.: C 61.41; H 5.98; N 5.73Found: C 61.38; H 5.91; N 5.83

Example 139Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylaminehydrochloride

In the same manner as done in Example 36 was treated 1.0 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Example 2. The product was 0.90 g oftrans-7chloro-5-(2chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylaminehydrochloride as plate crystals, m.p. 173°-175° C.

Elementary Analysis for C₂₁ H₂₄ Cl₂ N₂ O₂.HCl.H₂ O Calcd.: C 54.62; H5.89; N 6.06 Found: C 54.77; H 5.95; N 5.83

Example 140 Methyl N- trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!carbamoyl acetate

In 10 ml of N,N-dimethylformamide were dissolved 0.3 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylaminehydrochloride obtained in Example 139 and 0.12 g of monomethyl malonatepotassium salt. To the solution was added 0.13 g of diethylphosphorocyanate together with 0.11 ml of triethylamine underice-cooling. After stirring for 30 minutes at room temperature, thereaction mixture was subjected to extraction with 100 ml of water and100 ml of ethyl acetate. The ethyl acetate layer was washed with 1N HCland with a sodium bicarbonate aqueous solution, and dried over anhydrousmagnesium sulfate. The solvent ethyl acetate was then evaporated offunder reduced pressure. The residue was purified by silica-gel columnchromatography (eluent, hexane:ethyl acetate=1:1) to give 0.28 g ofmethyl N- trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!carbamoyl acetate asan oily product.

IRν_(Max) ^(Neat) cm⁻¹ 3330 (NH); 1740, 1670 (C═O)

¹ H-NMR (200 MHz, CDCl₃) δ: 0.94 (9H,s,Bu^(t)), 3.28 (2H,s), 3.38(1H,d,J=13.9 Hz), 3.74 (3H,s), 3.7-3.85(2H,m), 3.99(1H,t,J=6.1 Hz),4.54(1H,d,J=13.9 Hz), 6.25(1H,s), 6.52(1H,d,J=1.9 Hz), 7.2-7.9(7H,m,NH)

Example 141 N-Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!carbamoylacetic acid

In 5 ml of ethanol was dissolved 0.28 g of methyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!carbamoyl acetate obtained inExample 140. To the solution was added 2 ml of 1N sodium hydroxide andthe mixture was stirred for 10 minutes at room temperature. The reactionmixture was acidified with 50 ml of 1N hydrochloric acid and thensubjected to extraction with 50 ml of ethyl acetate. The ethyl acetatelayer was washed with water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to afford 0.23 g of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!carbamoylacetic acid as plate crystals, m.p. 135°-138° C.

Elementary analysis for C₂₄ H₂₆ Cl₂ N₂ O₅ : Calcd.: C 58.43; H 5.31; N5.68 Found: C 58.48; H 5.42; N 5.52

Example 142 Tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine3-methyl!aminoacetate

A mixture of 2.5 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylaminehydrochloride obtained in Example 139, 0.93 ml of ethyl chloroacetate,1.87 g of potassium carbonate, and 50 ml of acetonitrile was heated andrefluxed overnight. The reaction mixture was concentrated under reducedpressure and the concentrate was extracted with 100 ml of water and 150ml of ethyl acetate. The organic layer was washed with water and driedover anhydrous magnesium sulfate. Ethyl acetate was evaporated underreduced pressure to give 1.95 g of tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetateas an oily product.

IRν_(Max) ^(Neat) cm⁻¹ : 3330 (NH); 1735, 1675 (C═O)

1H-NMR (200 MHz, CDCl3) δ: 0.94 (9H,s,But), 1.44 (9H,s, But), 3.00(1H,dd,J=12.2,6.4 Hz), 3.11 (1H,dd,J=12.2,6.2 Hz), 3.33(2H,s),3.36(1H,d,J=14.0 Hz), 4.04(1H,t,J=6.3 Hz), 4.52(1H,d,J=14.0 Hz),6.26(1H,s), 6.52(1H,d,J=1.8 Hz), 7.2-7.85(6H,m)

Example 143 N-Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoaceticacid hydrochloride

In 15 ml of 4N HCl-dioxane solution was dissolved 0.3 mg of tert-butylN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetateobtained in Example 142. After stirring for 8 hours at room temperature,the reaction mixture was concentrated under reduced pressure. Theaddition of hexane and ethyl acetate to the residue yielded 0.23 g ofpowdered 'N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoaceticacid hydrochloride.

Elementary analysis for C₂₃ H₂₆ Cl₂ N₂ O₄.HCl Calcd.: C 55.05; H 5.42; N5.58 Found: C 55.38; H 5.77; N 5.39

¹ H-NMR spectrum (200 MHz, d₆ -DMSO) δ: 0.89(9H,s,Bu^(t)),3.2-3.55(2H,m), 3.68(1H,d,J=14.0 Hz), 3.88(2H,s), 4.32(1H,d,J=14.0 Hz),4.3-4.5(1H,m), 6.19(1H, s), 6.39(1H,d,J=2.4 Hz), 7.5-8.1(6H,m).

Example 144 Tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methansulfonylaminoacetate

In 5 ml of N,N-dimethylformamide was dissolved 0.44 g of tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetateobtained in Example 142. To the solution was added 0.072 ml ofmethanesulfonyl chloride and 0.14 ml of triethylamine under ice-cooling.After stirring for 30 minutes at room temperature, the reaction mixturewas subjected to extraction with 100 ml of water and 100 ml of ethylacetate. The ethyl acetate layer was washed with 5% potassium bisulfatesolution and with a sodium bicarbonate aqueous solution and dried overanhydrous magnesium sulfate. Ethyl acetate was evaporated off underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:acetate=3:1) to afford 0.37 g of tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonylaminoacetateas prisms, m.p. 178°-180° C.

Elementary analysis for C₂₈ H₃₆ Cl₂ N₂ O₆ S Calcd.: C 56.09; H 6.05; N4.67 Found: C 55.92; H 6.06; N 4.47

Example 145 N-Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonylaminoaceticacid

In 20 ml of 4N HCl-dioxane solution was dissolved 0.25 g of tert-butylN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonylaminoacetateobtained in Example 144. After stirring for 8 hours at room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue was treated with hexane and ethyl acetate to give 0.21 g of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!N-methanesulfonylaminoaceticacid as prisms, m.p. 236°-238° C.

Elementary analysis for C₂₄ H₂₈ Cl₂ N₂ O₆ S Calcd.: C 53.04; H 5.19; N5.15 Found: C 53.32; H 5.42; N 5.02

Example 146 Tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-(p-toluensulfonyl)aminoacetate

In 10 ml of N,N-dimethylformamide was dissolved 0.5 g of tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetate obtained in Example 142. To thesolution was added 0.22 g of p-toluenesulfonyl chloride together with0.16 ml of triethylamine under ice-cooling.

The mixture was stirred for one hour at room temperature and thensubjected to extraction with 100 ml of water and 100 ml of ethylacetate. The ethyl acetate layer was washed with 5% potassium bisulfatesolution and with sodium bicarbonate aqueous solution, dried overanhydrous magnesium sulfate. The solvent was evaporated off underreduced pressure. The residue was purified by column chromatographyusing silica gel (eluent, hexane:ethyl acetate=5:1) to afford tert-butylN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-(p-toluenesulfonyl)aminoacetateas an oily product.

IRν_(Max) ^(Neat) cm⁻¹ : 1740, 1670(C═O)

¹ H-NMR (200 MHz, CDC₁₃) δ: 0.92 (9H,s,Bu^(t)), 2.39(3H,s),3.36(1H,d,J=14.0 Hz), 3.66(1H,dd,J=15.6,6.4 Hz), 3.84(1H,dd, J=15.6,5.9Hz), 3.98(1H,d,J=18.4 Hz), 4.2-4.3(1H,m), 4.29(1H, d,J=18.4 Hz)4.45(1H,d,J=14.0 Hz), 6.20(1H,s), 6.46(1H,s, J=2.1 Hz), 7.15-7.7(10H,m)

Example 147 N-Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-(p-toluensulfonyl)aminoaceticacid

In 15 ml of 4N HCl-dioxane solution was dissolved 0.5 g of tert-butyl N-trans-7-chloro-5-(2chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-(p-toluensulfonyl)aminoacetateobtained in Example 146. After stirring for 4 hours at room temperature,the reaction solution was concentrated under reduced pressure. Theresidue was treated with hexane and diethyl ether to afford 0.41 g of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-(p-toluensulfonyl)aminoaceticacid as needles, m.p.132°-134° C.

Elementary analysis for C₃₀ H₃₂ Cl₂ N₂ O₆ S: Calcd.: C 58.16; H 5.21; N4.52 Found: C 58.01; H 5.32; N 4.55

Example 148 Tert-butyl N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetate

In 10 ml of N,N-dimethylformamide was dissolved 0.5 g of tert-butyl N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetateobtained in Example 142. To the solution was added 0.082 ml of acetylchloride and 0.16 ml of triethylamine under ice-cooling.

The mixture was stirred for 30 minutes at room temperature and thensubjected to extraction with 100 ml of water and 100 ml of ethylacetate. The ethyl acetate layer was washed with 5% potassium bisulfatesolution and with a sodium bicarbonate aqueous solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified on a silica gel column (eluent, hexane:ethylacetate=1:1) to give 0.5 g of tert-butyl N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro4,1-benzoxazepine-3-methyl!aminoacetateas an oily product.

IRν_(Max) ^(Neat) cm⁻¹ : 1740, 1670 (C═O)

¹ H-NMR (200 MHz, CDCl₃) δ: 0.92 and 0.94 (9H,each s,Bu^(t)), 1.95 and2.15 (3H,each s,Bu^(t)), 3.35 and 3.38 (1H,each d,J=14.0 Hz), 3.7-4.3(5H,m), 4.45 and 4.48 (1H,each d,J=14.0 Hz), 6.23 and 6.28 (1H, each s),6.45-6.55 (1H, m), 7.3-7.8 (6H, m).

Example 149 N-Acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoaceticacid

In 20 ml of 4N HCl-dioxane solution was dissolved 0.5 g of tert-butylN-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoacetateobtained in Example 148. After stirring overnight at room temperature,the mixture was concentrated under reduced pressure. The concentrate wastreated with hexane and diethylether to afford 0.37 g of powderyN-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminoaceticacid.

Elementary analysis for C₂₅ H₂₈ Cl₂ N₂ O₅ : Calcd.: C 59.18; H 5.56; N5.52 Found: C 59.36; H 5.70; N 5.50

¹ H-NMR spectrum (200 MHz, CDCl₃) δ: 0.92 and 0.94 (9H, each s,Bu^(t)),2.00 and 2.20 (3H, each s), 3.3-3.5 (1H, m), 3.7-4.5 (6H, m), 6.22 and6.28 (1H, each s), 6.45-6.55 (1H, m), 7.3-7.8 (6H, m)

Example 150 Methyl ester of 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminomethylbenzoicacid

(A) In 30 ml of acetonitrile was mixed 1.0 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylaminehydrochloride obtained in Example 139 with 0.6 g of methyl4-bromomethylbenzoate and 0.75 g of potassium carbonate. The mixture wasrefluxed by heating for 2 hours. After the addition of 0.2 g of methyl4-bromomethylbenzoate, reflux was confined by heating for 5 hours,followed by concentration under reduced pressure. The concentrate wasextracted with 100 ml of water and 150 ml of ethyl acetate. The ethylacetate layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was evaporated off under reduced pressure and theresidue was purified by silica gel column chromatography (eluent,hexane:ethyl acetate=10:1-1:2) to yield 0.15 g of methyl ester of 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminomethylbenzoicacid as prisms, m.p. 171° to 173° C.

Elementary analysis for C₃₀ H₃₂ Cl₂ N₂ O₄ : Calcd.: C 64.87; H 5.81; N5.04 Found: C 64.88; H 5.97; N 4.76

(B) In 20 ml of ethanol was dissolved 0.45 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methylaminehydrochloride obtained in Example 139. To the solution was added 0.19 gof terephthalaldehydic acid methyl ester together with 0.5 ml of aceticacid. After stirring for 30 minutes at room temperature, 82 mg of sodiumcyanoborohydride was added to the mixture. After further stirring for 2hours at room temperature, the mixture was concentrated under reducedpressure and the concentrate was extracted with 100 ml of water and 100ml of ethyl acetate. The organic layer was washed with water and driedover anhydrous magnesium sulfate. The organic solvent was evaporated offunder reduced pressure and the residue was purified by columnchromatography using silica gel (eluent, hexane:ethyl acetate=1:1) toyield 0.31 g of methyl ester of 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminomethylbenzoicacid.

Example 151 Methyl ester of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonyl!aminomethylbenzoicacid

In 5 ml of N,N-dimethylformamide was dissolved 0.3 g of methyl ester of4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!aminomethylbenzoicacid obtained in Example 150. To the solution were added 0.05 ml ofmethanesulfonyl chloride and 0.09 ml of triethylamine. After stirringfor one hour at room temperature, the reaction mixture was subjected toextraction with 100 ml of water and 100 ml of ethyl acetate. The ethylacetate layer was washed with 1N hydrochloric acid and with a sodiumbicarbonate aqueous solution, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent, hexane:ethyl acetate=2:1) toafford 0.27 g of methyl ester of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonyl!aminomethylbenzoicacid as needles, m.p. 173° to 174° C.

Elementary analysis for C₃₁ H₃₄ Cl₂ N₂ O₆ S: Calcd.: C 58.77; H 5.41; N4.42 Found: C 58.59; H 5.68; N 4.19

Example 152 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonyl!aminomethylbenzoicacid

In 10 ml of methanol was dissolved 0.17 g of methyl ester of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl!-N-methanesulfonyl!aminomethylbenzoicacid obtained in Example 151. After the addition of 4 ml of 1N sodiumhydroxide the solution was stirred for one hour at 60° C. The reactionmixture was then acidified with 50 ml of 1N hydrochloric acid andsubjected to extraction with 50 ml of ethyl acetate. The ethyl acetatelayer was washed with water, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give 0.16 g of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methyl-N-methanesulfonyl!aminomethylbenzoicacid as prisms, m.p. 235° to 237° C.

Elementary analysis for C₃₀ H₃₂ Cl₂ N₂ O₆ S: Calcd.: C 58.16; H 5.21; N4.52 Found: C 58.25; H 5.49; N 4.29

Example 153Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol

In 200 ml of tetrahydrofuran was dissolved 14.7 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Example 2 and 4.51 ml of N-methylmorpholine. To thesolution was added 3.92 ml of ethyl chlorocarbonate at -10° C; themixture was then stirred for 15 minutes. After the addition of 3.86 g ofsodium borohydride, 200 ml of methanol was added dropwise to thesolution. The mixture was stirred for one hour at room temperature andthen concentrated. After the addition of 200 ml of 1N hydrochloric acid,the concentrate was extracted with 200 ml of ethyl acetate. The organiclayer was washed with a saturated sodium bicarbonate aqueous solutionand dried over anhydrous magnesium sulfate. The solvent was evaporatedoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (eluent, hexane:ethyl acetate=1:1) to yield 14.2 goftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanolas colorless crystals, m.p. 157° to 159° C.

Elementary analysis for C₂₂ H₂₅ Cl₂ NO₃ : Calcd.: C 62.56; H 5.97; N3.32 Found: C 62.30; H 6.02; N 3.17

Example 154 Ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid

(1)Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde

To 25 ml of dichloromethane solution containing 0.70 ml of oxalylchloride was added 5 ml of dichloromethane solution containing 0.71 mlof dimethylsulfoxide at -78° C., followed by stirring for 5 minutes. Tothe solution was slowly added 10 ml of dichloromethane solutioncontaining 1.69 g oftrans-7-chloro-5-(2chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanolobtained in Example 160, followed by stirring for 15 minutes at -78° C.To the reaction mixture was added 2.79 ml of triethylamine and themixture was further stirred for one hour at 0° C. and for 1.5 hours atroom temperature. After the addition of 100 ml of water, extraction wasperformed with 100 ml of dichloromethane. The dichloromethane layer waswashed with saturated saline and dried over anhydrous magnesium sulfate.The solvent was evaporated off under reduced pressure. The residue waspurified by column chromatography using silica gel (eluent, hexane:ethylacetate=1:1) to give 1.08 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehydeas light-yellow crystals, m.p.173° to 176° C.

Elementary analysis for C₂₂ H₂₃ Cl₂ NO₃.0.5H₂ O: Calcd.: C 61.55; H5.63; N 3.26 Found: C 61.27; H 5.49; N 3.17

(2) Ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid

To 40 ml of ethanol containing 1.12 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehydeobtained in Example 161 (1) and 0.56 g of glycine ethyl esterhydrochloride was added 10 ml of ethanol containing 0.13 g of sodiumcyanoborohydride dropwise over 1.5 hours. After additional 3-hourstirring, the reaction mixture was subjected to extraction with 200 mlof water and 200 ml of ethyl acetate. The ethyl acetate layer was washedwith saturated saline and dried over anhydrous magnesium sulfate. Thesolvent was evaporated off under reduced pressure and the residue waspurified by silica gel column chromatography (eluent, ethyl acetate) toafford 0.75 g of amorphous solid ethyl ester ofN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro4,1-benzoxazepine-3-ethyl!aminoaceticacid.

Elementary analysis for C₂₆ H₃₂ Cl₂ N₂ O₄ : Calcd.: C 61.54; H 6.36; N5.52 Found: C 61.16; H 6.29; N 5.56

¹ H-NMR (CDCl₃) δ: 0.93 (9H, s, Bu^(t)), 1.26 (3H, t, J=7.2 Hz),1.90-2.15 (3H, m), 2.76 (2H, dd, J=7.2, 6.6 Hz), 3.38 (1H, d, J=13.9Hz), 3.38 (2H, s) 4.03 (1H, dd, J=6.6, 6.2 Hz), 4.17 (2H, q, J=7.2 Hz),4.51 (1H, d, J=13.9 Hz), 6.24 (1H, s), 6.51 (1H, d, J=1.6 Hz), 7.30-7.50(5H, m), 7.70-7.80 (1H, m)

Example 155 Ethyl ester of N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid

In 15 ml of N,N-dimethylformamide was dissolved 0.15 g of ethyl ester ofN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoacetateobtained in Example 154. To the solution were added 0.031 ml of acetylchloride and 0.050 ml of triethylamine under ice-cooling. After stirringfor 30 minutes under ice-cooling, the reaction mixture was subjected toextraction with 40 ml of water and 40 ml of ethyl acetate. The ethylacetate layer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The solvent was evaporated off under reducedpressure. The residue was purified by column chromatography using silicagel (eluent, hexane:ethyl acetate=1:3) to give 0.15g of amorphous solidethyl ester of N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid.

Elementary analysis for C₂₈ H₃₄ Cl₂ N₂ O₅.0.4H₂ O: Calcd.: C 60.41; H6.30; N 5.03 Found: C 60.44; H 6.43; N 4.96

¹ H-NMR (CDCl₃) δ: 0.93 and 0.94 (9H, each s, Bu^(t)), 1.20-1.32 (3H,m), 1.95-2.20 (2H, m), 1.95 and 2.13 (total 3H, each s), 3.32-3.68 (3H,m), 3.90-4.27 (5H, m), 4.48 and 4.50 (total 1H, each d, J=13.8 Hz), 6.22and 6.24 (total 1H, each s), 6.50 and 6.53 (total 1H, each d, J=2.0 Hz),7.29-7.50 (5H, m), 7.65-7.80 (1H, m)

Example 156 N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid

To 5 ml of methanol containing 0.11 g of ethyl ester of N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoacetateobtained in Example 155 was added 1 ml of 0.5M potassium carbonateaqueous solution. After stirring for 30 minutes at 60° C., the reactionmixture was acidified with 0.5 ml of 1N hydrochloric acid and subjectedto extraction with 20 ml of water and 20 ml of ethyl acetate. The ethylacetate layer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The solvent was evaporated off under reducedpressure. The residue was treated with ether to yield 0.07 g of whitepowdery N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid, m.p. 210° to 212° C.

Elementary analysis for C₂₆ H₃₀ Cl₂ N₂ O₅ : Calcd.: C 59.89; H 5.80; N5.37 Found: C 59.78; H 5.85; N 5.13

Example 157 Ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonylaminoaceticacid

In 5 ml of N,N-dimethylformamide was dissolved 0.15 g of ethyl ester ofN-trans-7-chloro-5-(2-chlorophenyl)-l1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoacetateobtained in Example 154. To the solution were added 0.028 ml ofmethanesulfonyl chloride and 0.050 ml of triethylamine underice-cooling. After stirring for 30 minutes under ice-cooling, extractionwas performed with 40 ml of water and 40 ml of ethyl acetate. The ethylacetate layer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The solvent was evaporated off under reducedpressure, and the residue was purified on a silica gel columnchromatography (eluent, hexane:ethyl acetate=2:1) to afford 0.12 g ofethyl ester ofN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulphonylaminoaceticacid as a white powdery product, m.p. 134° to 135° C.

Elementary analysis for C₂₇ H₃₄ Cl₂ N₂ O₆ S: Calcd.: C 55.38; H 5.85; N4.78 Found: C 55.66; H 5.98; N 4.61

Example 158 N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonylaminoaceticacid

In the same manner as in Example 156 was hydrolyzed 0.12 g of ethylester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonylaminoaceticacid obtained in Example 157 to give 0.10 g of white powdery N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonylaminoaceticacid, m.p. 135° to 137° C.

Elementary analysis for C₂₅ H₃₀ Cl₂ N₂ O₆ S.0.5H₂ O: Calcd.: C 53.00; H5.52; N 4.94 Found: C 53.25; H 5.78; N 4.71

Example 159 Ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-(p-toluensulfonyl)aminoaceticacid

In 5 ml of N,N-dimethylformamide was dissolved 0.15 g of ethyl ester ofN-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminoaceticacid obtained in Example 154. To the solution was added 0.069 g ofp-toluenesulfonyl chloride together with 0.050 ml of triethylamine underice-cooling. After stirring for 30 minutes under ice-cooling, thereaction mixture was subjected to extraction with 40 ml of water and 40ml of ethyl acetate. The ethyl acetate layer was washed with saturatedsaline and dried over anhydrous magnesium sulfate. Ethyl acetate wasevaporated off under reduced pressure. The residue was purified bycolumn chromatography using silica gel (eluent, hexane:ethylacetate=3:1) to yield 0.17 g of amorphous ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluenesulfonylaminoaceticacid.

Elementary analysis for C₃₃ H₃₈ Cl₂ N₂ O₆ S: Calcd.: C 59.91; H 5.79; N4.23 Found: C 60.25; H 6.01; N 4.04

¹ H-NMR (CDCl₃) δ: 0.94 (9H, s, Bu^(t)), 1.15 (3H, t, J=7.2 Hz),1.90-2.30 (2H, m), 2.41 (3H, s), 3.20-3.60 (2H, m), 3.41 (1H, d, J=140Hz), 3.97-4.18 (5H, m), 4.50 (1H, d, J=14.0 Hz), 6.23 (1H, s), 6.52 (1H,s), 7.21-7.50 (7H, m), 7.62-7.80 (3H, m)

Example 160 N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluensuilfonylaminoaceticacid

In the same manner as in Example 156, 0.15 g of ethyl ester of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluensulfonylaminoaceticacid was hydrolyzed to yield 0.11 g of N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl-N-p-toluensulfonylaminoaceticacid as white powder, m.p. 274° to 277° C.

Elementary analysis for C₃₁ H₃₄ Cl₂ N₂ O₆ S: Calcd.: C 58.77; H 5.41; N4.42 Found: C 58.70; H 5.59; N 4.13

Example 161 Methyl ester of 4N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminomethylbenzoicacid

A mixture of 0.42 g oftrans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehydeobtained in Example 154 (1), 0.30 g of 4-aminomethylbenzoic acid methylester hydrochloric acid salt, and 30 ml of ethanol was stirred for 2hours at room temperature. Subsequently 5 ml of ethanol containing 0.06g of sodium cyanoborohydride was slowly added dropwise to the mixture.After stirring for 2 hours, the reaction mixture was subjected toextraction with 100 ml of water and 100 ml of ethyl acetate. The ethylacetate layer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The organic solvent was evaporated off under reducedpressure. The residue was purified by column chromatography using silicagel (eluent, ethyl acetate) to give amorphous methyl ester of 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminomethylbenzoicacid.

Elementary analysis for C₃₁ H₃₄ Cl₂ N₂ O₄ : Calcd.: C 65.38; H 6.02; N4.92 Found: C 64.99; H 6.11; N 5.19

¹ H-NMR(CDCl₃) δ: 0.94 (9H, s, Bu^(t)), 1.98-2.26 (3H, m), 2.65-2.90(2H, m), 3.38 (1H, d, J=14.0 Hz), 3.83 (2H, s), 3.91 (3H, s), 4.06 (1H,t, J=6.2 Hz), 4.49 (1H, d, J=14.0 Hz), 6.21 (1H, s), 5.51 (1H, d, J=2.0Hz), 7.26-7.62H, m), 7.92-8.02 (2H, m)

Example 162 Methyl ester of 4- N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!!aminomethylbenzoicacid

In the same manner as in Example 155, 0.13 g of methyl ester of 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminomethylbenzoicacid obtained in Example 161 was treated to yield 0.13 g of amorphousmethyl ester of 4- N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!!aminomethylbenzoicacid.

Elementary analysis for C₃₃ H₃₆ Cl₂ N₂ O₅ : Calcd.: C 64.81; H 5.93; N4.58 Found: C 65.14; H 6.12; N 4.11

¹ H-NMR (CDCl₃) δ: 0.93 (9H, s, Bu^(t)), 2.00-2.20 (2H, m), 2.02 and2.18 (total 3H, each s), 3.20-3.60 (3H, m), 3.78-4.00 (1H, m), 3.91 and3.93 (total 3H, each s), 4.42-4.76 (3H, m), 6.21 (1H, s), 6.50 (1H, d,J=1.8 Hz), 7.17-7.70 (8H, m), 7.95 (1H, d, J=8.0 Hz), 8.02 (1H, d, J=8.2Hz)

Example 163 4- N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!!aminomethylbenzoicacid

In the same manner as in Example 156, 0.10 g of methyl ester of 4-N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminomethylbenzoicacid obtained in Example 162 was hydrolyzed to afford 0.08 g of whitepowdery 4- N-acetyl-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-ozo-1,2,3,5-tetrahydro-4,1-benzoazepine-3-ethyl!!aminomethylbenzoicacid, m.p. 242° to 244° C.

Elementary analysis for C₃₂ H₃₄ Cl₂ N₂ O₅ : Calcd.: C 64.32; H 5.74; N4.69 Found: C 64.34; H 5.87; N 4.66

Example 164 Methyl ester of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoazepine-3-ethyl!-N-methanesulfonyl!aminomethylbenzoic acid

In the same manner as in Example 157, 0.13 g of methyl ester of 4-N-trans-7chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminomethylbenzoicacid obtained in Example 161 was treated to give 0.12 g of methyl esterof ⁴ - N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonyl!aminomethylbenzoicacid as colorless crystals, m.p. 172° to 174° C.

Elementary analysis for C₃₂ H₃₆ Cl₂ N₂ O₆ S: Calcd.: C 59.35; H 5.60; N4.33 Found: C 59.15; H 5.79; N 4.16

Example 165 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonyl!aminomethylbenzoicacid

In the same manner as in Example 156, 0.09 g of methyl ester of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonyl!aminomethylbenzoicacid obtained in Example 164 was hydrolyzed to afford 0.06 g of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-methanesulfonyl!aminomethylbenzoicacid as colorless crystals, m.p. 185° to 187° C.

Elementary analysis for C₃₁ H₃₄ Cl₂ N₂ O₆ S.0.5H₂ O: Calcd.: C 57.95; H5.49; N 4.36 Found: C 58.30; H 5.83; N 4.19

Example 166 Methyl ester of 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluenesulfonyl!aminomethylbenzoicacid

In the same manner as in Example 159, 0.13 g of methyl ester of 4-N-trans-7-chloro-5-(2chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!aminomethylbenzoicacid obtained in Example 161 was treated to give 0.14 g of methyl esterof 4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluenesulfonyl!aminomethylbenzoicacid as colorless crystals, m.p. 145° to 147° C.

Elementary analysis for C₃₈ H₄₀ Cl₂ N₂ O₆ S: Calcd.: C 63.07; H 5.57; N3.87 Found: C 63.09; H 5.50; N 3.93

Example 167

4- N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluenesulfonyl!aminomethylbenzoicacid

In the same manner as in Example 156, 0.12 g of methyl ester of 4-N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluenesulfonyl!aminomethylbenzoicacid obtained in Example 166 was hydrolyzed to afford 0.09 g of 4 N-trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl!-N-p-toluenesulfonyl!aminomethylbenzoicacid as colorless powder, m.p. 265° to 268° C.

Elementary analysis for C₃₇ H₃₈ Cl₂ N₂ O₆ S: Calcd.: C 62.62; H 5.40; N3.95 Found: C 62.67; H 5.36; N 3.96

Example 168 Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine

In the same manner as in Examples 104,trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid obtained in Example 2 was treated to afford the followingcrystalline compounds:

(1)Trans-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine,m.p. 171° to 172° C.

Elementary analysis for C₂₄ H₂₅ Cl₂ N₃ O₃ : Calcd.: C 60.77; H 5.31; N8.86 Found: C 60.68; H 5.24; N 8.62

(2) Trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-(tetrazol-5-yl)methylaminocarbonylmethyl!-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine,m.p. 251° to 252° C.

Elementary analysis for C₂₄ H₂₆ Cl₂ N₆ O₃ : Calcd.: C 55.71; H 5.06; N16.24 Found: C 55.38; H 5.22; N 16.03

Materials and intermediate compounds included in Examples are listed inTables 74 to 88.

2-aminobenzophenones as the starting material can be synthesized by, orin accordance with, the method described in D. A. Walsh, Synthesis, 677(1980) or the method cited in said reference.

Example 169 (3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (I) and (3R,5S)-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (II)

(1) N-(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester and N-(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester

To a solution oftrans-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (3.0 g) and L-alanine tert-butyl ester hydrochloride (1.51 g) inN,N-dimethylformamide (20 ml) were added to diethylphosphorocyanidate(1.43 g) and triethylamine (2.42 ml) at 0° C. After being stirred for 30min. at room temperature, the mixture was diluted with water andextracted with ethyl acetate (50 ml). The mixture was washed with 1Nhydrochloric acid (20 ml×2) and aqueous sodium bicarbonate (20 ml×2),dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=3:1-1:1) to give firstly N-(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester (1.55 g) as colorless crystals (mp 74°-79° C.).

Anal. Calcd. for C₃₀ H₃₉ ClN₂ O₆ Calcd: C, 64.55; H, 7.03; N, 5.01Found: C, 64.05; H, 7.27; N, 4.72.

From the second fraction was obtained N- (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester (1.8 g) as an oil.

¹ H-NMR (CDCl₃) δ: 0.93(9H, s), 1.35(3H, d, J=7.0 Hz), 1.45(9H, s),2.69(1H, dd, J=14.6, 5.7 Hz), 2.87(1H, dd, J=14.6, 7.2 Hz), 3.34(1H, d,J=14.0 Hz), 3.62(3H, s), 4.3-4.5(2H, m), 4.49(1H, d, J=14.0 Hz),6.27(1H, s), 6.3-6.4(1H, brd), 6.6-6.7(1H, m), 6.8-7.7(6H, m).

(2) N-(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanineA solution of N-(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester (1.4 g) in 4N hydrogen chloride/dioxane solution (20ml) was stirred for 5 h. The mixture was diluted with water (50 ml) andextracted with ethyl acetate (50 ml). The mixture was washed with water,dried over magnesium sulfate and concentrated in vacuo to give N-(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine(1.20 g) as an amorphous powder.

Anal. Calcd. for C₂₆ H₃₁ ClN₂ O₆ Calcd: C, 62.09; H, 6.21; N, 5.57Found: C, 62.38; H, 6.51; N. 5.34.

¹ H-NMR (CDCl₃) 67 : 0.93(9H, s), 1.44(3H, d, J=7.2 Hz), 2.71(1H, dd,J=14.4, 5.5 Hz), 2.93(1H, dd, J=14.4, 7.6 Hz), 3.35(1H, d, J=13.9 Hz),3.63(3H, s), 4.3-4.4(1H, m), 4.4-4.6(2H, m), 6.27(1H, s), 6.63(1H, d,J=1.9 Hz), 6.71(1H, brd, J=6.8 Hz), 6.8-7.7(6H, m).

(3) N-(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine

N-(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester (1.8 g) was converted to N-(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine(1.35 g, an amorphous powder) in a similar manner to that described inexample 169 (2).

Anal. Calcd. for C₂₆ H₃₁ ClN₂ O₆ Calcd: C, 62.09; H, 6.21; N, 5.57Found: C, 61.69; H, 6.23; N, 5.38.

¹ H-NMR(CDCl₃) δ: 0.93(9H, s), 1.43(3H, d, J=7.2 Hz), 2.73(1H, dd,J=14.6, 5.8 Hz), 2.89(1H, dd, J=14.6, 5.8 Hz), 3.35(1H, d, J=14.0 Hz),3.63(3H, s), 4.38(1H, t, J=7.4 Hz), 4.45-4.6(2H, m), 6.28(1H, s),6.55(1H, brd, J=6.8 Hz), 6.64(1H, d, J=2.0 Hz), 6.8-7.7(6H, m).

(4)(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (I)

A mixture of N-(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine(1.0 g), concentrated hydrochloric acid (10 ml) and methanol (10 ml) wasrefluxed for 24 h. After cooling, the mixture was diluted with water andextracted with ethyl acetate (50 ml). The extract was washed with water,dried over magnesium sulfate and concentrated in vacuo. A mixture of theresidue, methyl iodide (0.19 ml), potassium carbonate (0.55 g) andN,N-dimethylformamide (20 ml) was stirred for 1 h. The mixture wasdiluted with water and extracted with ethyl acetate (50 ml). The extractwas washed with 1N hydrochloric acid (20 ml×2) and aqueous sodiumbicarbonate, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=3:1) to give methyl(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(0.51 g). A mixture of the methyl ester (0.51 g), potassium carbonate(0.32 g), methanol (10 ml) and water (10 ml) was refluxed for 2.5 h. Themixture was acidified with 1N hydrochloric acid (20 ml) and extractedwith ethyl acetate (50 ml). The extract was washed with water, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=2:1-dichloromethane:methanol=2:1) to give(3S,5R)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.46 g) as crystals (mp 179°-183° C.).

α!_(D) ²⁵ +248.70° (c=0.45, MeOH)

Anal. Calcd. for C₂₃ H₂₆ ClNO₅.H₂ O Calcd: C, 61.40; H, 6.27; N, 3.11Found: C, 61.12; H, 5.99; N, 3.28.

(5)(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (II)

N-(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alanine(1.0 g) was converted to(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.32 g) in a similar manner to that described in example 169 (3).

mp 176°-180° C.

Anal. Calcd. for C₂₃ H₂₆ ClNO₅.1.5H₂ O Calcd: C, 60.19; H, 6.37; N, 3.05Found: C, 60.05; H, 5.88; N, 3.22.

α!_(D) ²⁵ -246.2° (c=0.45, MeOH)

Example170(3S,5R)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (I) and(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (II)

These compounds were prepared fromtrans-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid in a similar manner to that described in example 169.

(1) N-(3S,5R)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester colorless crystals (mp 120°-122° C.)

Anal. Calcd. for C₃₁ H₄₁ ClN₂ O₇.0.5H₂ O Calcd: C, 62.25; H, 7.08; N,4.68 Found: C, 62.45; H, 6.89; N, 4.68.

(2) N-(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester colorless crystals (mp 136°-137° C.)

Anal. Calcd. for C₃₁ H₄₁ ClN₂ O₇ 0.8H₂ O Calcd: C, 61.69; H, 7.11; N,4.64 Found: C, 61.60; H, 7.45; N. 4.58.

(3) N-(3S,5R)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninecolorless crystals (mp 182°-185° C.)

Anal. Calcd. for C₂₇ H₃₃ ClN₂ O₇ Calcd: C, 60.84; H, 6.24; N, 5.26Found: C, 60.78; H, 6.09; N, 4.99.

(4) N-(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninecolorless crystals (mp 137°-140° C.)

Anal. Calcd. for C₂₇ H₃₃ ClN₂ O₇.0.3C₆ H₁₄.0.3H₂ O Calcd: C, 61.11; H,6.77; N. 4.95 Found: C, 61.21; H, 6.91; N, 5.05.

(5)(3S,5R)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (I) colorless crystals (mp 227°-230° C.)

Anal. Calcd. for C₂₄ H₂₈ ClNO₆.0.5H₂ O Calcd: C, 61.21; H, 6.21; N, 2.97Found: C, 61.20; H, 6.07; N, 2.91.

α!_(D) ²⁴ +242.7° (c=0.41, MeOH)

(6)(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (II) colorless crystals (mp 218°-222° C.)

Anal. Calcd. for C₂₄ H₂₈ ClNO₆.0.75H₂ O Calcd: C, 60.63; H, 6.25; N,2.95 Found: C, 60.58; H, 6.05; N, 2.95.

α!_(D) ²⁴ -246.8° (c=0.43, MeOH)

Example 171 (3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (I) and(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (II)

(1) N-(3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-leucinemethyl ester and N- (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-leucinemethyl ester

To a solution oftrans-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (11.0 g) and L-leucine methyl ester hydrochloride (5.2 g) inN,N-dimethylformamide (50 ml) were added diethyl phosphorocyanidate (4.9g) and triethylamine (8.3 ml) at 0° C. After being stirred for 30 min.at room temperature, the mixture was diluted with water (200 ml) andextracted with ethyl acetate (300 ml). The extract was washed with 1Nhydrochloric acid (100 ml×2) and aqueous sodium bicarbonate (100 ml×2),dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=2:1-1:1) to give firstly N-(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-leucinemethyl ester (6.7 g) as colorless crystals (mp 93°-96° C.).

Anal. Calcd. for C₃₁ H₄₁ ClN₂ O₇.0.5H₂ O Calcd: C, 62.25; H, 7.08; N,4.68 Found: C, 62.38; H, 7.42; N, 4.43.

From the second fraction was obtainedN-(3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-leucinemethyl ester (6.5 g) as an oil.

¹ H-NMR(CDCl₃) δ: 0.8-1.1(15H, m), 1.5-1.75(1H, m), 2.70(1H, dd, J=14.4,6.0 Hz), 2.88(1H, dd, J=14.4, 6.6 Hz), 3.35(1H, d, J=14.0 Hz), 3.60(3H,s), 3.71(3H, s), 3.86(3H, s), 4.33(1H, t, J=6.2 Hz), 4.51(1H, d, J=14.0Hz), 4.5-4.7(1H, m), 6.21(1H, m), 6.45-6.7 (4H, m), 7.2-7.6(3H, m).

(2)(3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (I)

A mixture of N- (3S, 5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-leucinemethyl ester (1.0 g), concentrated sulfuric acid (4 ml) and methanol (20ml) was refluxed for 24 h. After cooling, the mixture was diluted withwater and extracted with ethyl acetate (50 ml). The extract was washedwith 1N hydrochloric acid (20 ml×2) and sodium bicarbonate (20 ml×2),dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=5:1)to give methyl(3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(0.22 g). A mixture of the methyl ester (0.22 g), potassium carbonate(0.13 g), methanol (10 ml), tetrahydrofuran (5 ml) and water (10 ml) wasrefluxed for 2 h. The mixture was acidified with 1N hydrochloric acidand extracted with ethyl acetate. The extract was washed with water,dried over magnesium sulfate and concentrated in vacuo to give(3S,5R)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.20 g) as colorless crystals (mp 233°-234° C.).

Anal. Calcd. for C₂₄ H₂₈ ClNO₆ Calcd: C, 62.40; H, 6.11; N, 3.03 Found:C, 62.28; H, 6.41; N, 2.89.

α!_(D) ²² +228.1° (c=0.51, MeOH)

(3)(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (II)

N-(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-leucinemethyl ester (6.0 g) was converted to(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.74 g) in a similar manner to that described in example 171(2).

Anal. Calcd. for C₂₄ H₂₈ ClNO₆ Calcd: C, 62.40; H, 6.11; N, 3.03 Found:C, 62.39; H, 6.20; N, 2.81.

α!_(D) ²² -232.5° (c=0.41, MeOH)

Example 172 sodium (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

To a suspension of(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (12 g) in methanol (200 ml) was added 1N aqueous sodium hydroxide(27.7 ml). After the acid was dissolved completely, the mixture wasconcentrated in vacuo. To the residue was added ethyl acetate (200 ml)and the mixture was concentrated in vacuo. The deposited crystals werecollected to give sodium(3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (11.8 g) as colorlesscrystals (mp >300° C.).

Anal. Calcd. for C₂₃ H₂₅ ClNO₅ Na.0.75H₂ O Calcd: C, 59.10; H, 5.71; N,3.00 Found: C, 59.27; H, 5.97; N, 2.75.

α!_(D) ²² -263.6° (c=0.64, MeOH)

Example 173 sodium(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (1.2 g) was converted to sodium(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(1.1 g) in a similar manner to that described in Example 172. mp>300° C.

Anal. Calcd. for C₂₂ H₂₂ ClNO₄ Na.H₂ O Calcd: C, 55.47; H, 5.08; N, 2.94Found: C, 55.41; H, 5.26; N, 2.83.

α!_(D) ²² -237.1° (c=0.57, MeOH)

Example 174 sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (30 g) was converted to sodium(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(31.9 g) in a similar manner to that described in Example 172.

mp >300° C.

Anal. Calcd. for C₂₄ H₂₇ ClNO₆ Na.1.5H₂ O Calcd: C, 56.42; H, 5.92; N,2.74 Found: C, 56.49; H, 6.02; N, 2.75.

α!_(D) ²³ -235.1° (c=0.60, MeOH)

Example 175 sodium(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (24 g) was converted to sodium(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(24.7 g) in a similar manner to that described in example 172.

mp >300° C.

Anal. Calcd. for C₂₄ H₂₇ ClNO₆ Na.0.75H₂ O Calcd: C, 57.95; H, 5.78; N,2.82 Found: C, 57.86; H, 6.08; N, 2.81.

α!_(D) ²³ -231.1° (c=0.70, MeOH)

Example 176trans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

(1) 2-amino-4'-benzyloxy-5-chloro-2'-methoxybenzophenone

A mixture of 4-bromo-3-methoxyphenol (21 g), benzyl bromide (13.5 ml),potassium carbonate (21.4 g) and acetone (200 ml) was stirred at roomtemperature for 24 h. The insoluble materials were removed by filtrationand the filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate 20:1) to give4-benzyloxy-2-methoxybromobenzene (25 g) as an oil.

¹ H-NMR(CDCl₃) δ: 3.85(3H, s), 5.04(2H, s), 6.47(1H, dd, J=8.6, 2.6 Hz),6.57(1H, d, J=2.6 Hz), 7.3-7.5(8H, m).

2-amino-4'-benzyloxy-5-chloro-2'-methoxybenzophenone (20.4 g) wasprepared from 4-benzyloxy-2-methoxybromobenzene according to theliterature (L. H. Sternbach et al., J. Org. Chem., 27, 378 (1962)).mp=97°-98° C.

Anal. Calcd. for C₂₁ H₁₈ ClNO₄ Calcd: C, 68.57; H, 4.93; N, 3.81Found:C, 68.62; H, 5.09; N, 3.65.

(2) 2-amino-α-(4-benzyloxy-2-methoxyphenyl)-5-chlorobenzyl alcohol

To a solution of 2-amino-4'-benzyloxy-5-chloro-2'-methoxybenzophenone(10 g) in methanol (100 ml) was added sodium borohydride (1.4 g). Afterbeing stirred for 24 h, the mixture was concentrated in vacuo. Theresidue was diluted with water (200 ml) and extracted with ethyl acetate(300 ml). The extract was washed with water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-2:1) to give2-amino-α-(4-benzyloxy-2-methoxyphenyl)-5-chlorobenzyl alcohol (9.5 g)as colorless crystals (mp=101°-103° C.).

Anal. Calcd. for C₂₁ H₂₀ ClNO₃ Calcd: C, 68.20; H, 5.41; N, 3.79 Found:C, 67.97; H, 5.42; N, 3.58.

(3) α-(4-benzyloxy-2-methoxyphenyl)-2-neopentylamino-5-chlorobenzylalcohol

A mixture of 2-amino-α-(4-benzyloxy-2-methoxyphenyl)-5-chlorobenzylalcohol (9.5 g), pivalaldehyde (3.35 ml), acetic acid (1.85 g) andethanol (200 ml) was stirred for 30 min. To the mixture was added sodiumcyanoborohydride (2.33 g) and the mixture was stirred for 24 h. Afterthe mixture was concentrated in vacuo, the residue was diluted withwater (200 ml) and extracted with ethyl acetate (200 ml). The extractwas washed with water, dried over magnesium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=5:1) to giveα-(4-benzyloxy-2-methoxyphenyl)-2-neopentylamino-5-chlorobenzyl alcohol(10.0 g) as a colorless oil.

¹ H-NMR(CDCl₃) δ: 0.91(9H, s), 2.82(2H, s), 3.10(1H, br), 3.85(3H, s),4.75(1H, br), 5.06(2H, s), 5.94(1H, s), 6.45-6.7(3H, m), 6.95-7.5(7H,m).

(4) ethyl 3- N- 4-chloro-2-(4-benzyloxy-α-hydroxy-2-methoxybenzyl)phenyl!-N-neopentylcarbamoyl!acrylate

A mixture ofα-(4-benzyloxy-2-methoxyphenyl)-2-neopentylamino-5-chlorobenzyl alcohol(10 g), fumaric acid chloride monomethyl ester (4.43 g), sodiumbicarbonate (6.28 g) and dichloromethane (200 ml) was stirred for 30min. The mixture was washed with water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1-2:1) to give ethyl 3- N-4-chloro-2-(4-benzyloxy-α-hydroxy-2-methoxybenzyl)-phenyl!-N-neopentylcarbamoyl!acrylate(12.0 g) as a colorless oil.

¹ H-NMR(CDCl₃) δ: 0.7-1.0(9H, m), 1.1-1.3(3H, m), 2.5-3.15(2H, m), 3.69,3.77(3H, each s), 3.9-4.5(3H, m), 4.95, 5.07(2H, each s), 5.9-6.85(5H,m), 6.95-7.9(10H, m).

(5) ethyltrans-5-(4-benzyloxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

To a mixture of ethyl 3- N-4-chloro-2-(4-benzyloxy-α-hydroxy-2-methoxybenzyl)-phenyl!-N-neopentylcarbamoyl!acrylate(12 g), potassium carbonate (5.9 g) and ethanol (150 ml) was stirred for24 h. After the mixture was concentrated in vacuo, the residue wasdiluted with water (200 ml) and extracted with ethyl acetate (200 ml).The extract was washed with water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to give ethyltrans-5-(4-benzyloxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(9.8 g) as needles (mp=130°-131° C.).

Anal. Calcd. for C₃₂ H₃₆ ClNO₆ Calcd: C, 67.90; H, 6.41; N, 2.47 Found:C, 67.73; H, 6.35; N, 2.33.

(6) ethyltrans-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

A solution of ethyltrans-5-(4-benzyloxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(7.0 g) and 1N hydrochloric acid (0.1 ml) in ethyl acetate (150 ml) washydrogenated over 10% Pd-C (50% wet, 1.0 g) under atmospheric pressureuntil the absorption of hydrogen stopped. The catalyst was removed byfiltration and the filtrate was concentrated in vacuo to give ethyltrans-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(5.6 g) as colorless crystals (mp 197°-199° C.).

Anal. Calcd. for C₂₅ H₃₀ ClNO₆ Calcd: C, 63.09; H, 6.35; N, 2.94 Found:C, 62.97; H, 6.57; N, 2.81.

(7) ethyltrans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

A mixture of ethyltrans-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(0.25 g), ethyl iodide (0.06 ml), potassium carbonate (0.15 g) andN,N-dimethylformamide (200 ml) was stirred for 3 h. The mixture wasdiluted with water (50 ml) and extracted with ethyl acetate (100 ml).The extract was washed with 1N hydrochloric acid and aqueous sodiumbicarbonate, dried over magnesium sulfate and concentrated in vacuo togive ethyltrans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(0.24 g) as colorless crystals (mp=164°-166° C.).

Anal. Calcd. for C₂₇ H₃₄ ClNO₆ Calcd: C, 64.34; H, 6.80; N, 2.78 Found:C, 64.18; H, 6.70; N, 2.74.

(8)trans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

A mixture of ethyltrans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(0.18 g), potassium carbonate (0.10 g), methanol (10 ml),tetrahydrofuran (10 ml) and water (5 ml) was refluxed for 1.5 h. Theresulting mixture was concentrated in vacuo, acidified with 1Nhydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml). Theextract was washed with water, dried over magnesium sulfate andconcentrated in vacuo to givetrans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid as colorless crystals (mp=230°-232° C.).

Anal. Calcd. for C₂₅ H₃₀ ClNO₆ Calcd: C, 63.09; H, 6.35; N, 2.94 Found:C, 62.92; H, 6.60; N, 3.01.

Example 177 (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (2.2 g) was coupled with L-alanine tert-butyl ester in a similarmanner to that described in example 169 to give N-(3S,5R)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester (1.0 g) and N-(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine3-acetyl!-L-alanine tert-butyl ester (1.1 g).

N-(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!-L-alaninetert-butyl ester (0.8 g) was converted to(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (0.33 g) in a similar manner to that described in example 169 (2).colorless crystals (mp=162°-165° C.)

Anal. Calcd. for C₂₅ H₃₀ ClNO₆ Calcd: C, 63.09; H, 6.35; N, 2.94 Found:C, 62.92; H, 6.60; N, 3.01.

α!_(D) ²³ -212.0° (c=0.94, MeOH)

Example 178 sodium(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate

(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (3.65 g) was converted to sodium(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate(3.54 g) in a similar manner to that described in example 172.

colorless crystals (mp=230°-250° C., dec.)

Anal. Calcd. for C₂₅ H₂₉ ClNO₆ Na Calcd: C, 58.81; H, 6.00; N, 2.74Found: C, 58.91; H, 6.24; N, 2.71.

α!_(D) ²² -218.8° (c=0.48, MeOH)

    ______________________________________    Squalene synthase inhibitory activity (in vitro)    Example  Isomer form                        rat enzyme human hepG2 enzyme    No.      No.        IC.sub.50 (μM)                                   IC.sub.50 (μM)    ______________________________________    169      I          43%.sup.1    169      II         0.026      0.011    170      I          7.7    170      II         0.017      0.011    171      I          15.8%.sup.1    171      II         0.022      0.0086    173                 0.067      0.020    177                 0.029      0.019    178                 0.041      0.022    ______________________________________     .sup.1 % Inhibition at 10.sup.-5 M.

                                      TABLE 74    __________________________________________________________________________     ##STR227##             m.p.        Elemental Analysis (Found)    X   Y    (°C.)                  Formula                         C      H     N    __________________________________________________________________________    5-F 2'-Cl     subjected to the next procedure without isolating    5-MeO        2'-Cl             oil         .sup.1 HNMR(CDCl.sub.3)δ: 3.59(3H, s),                         5.88(2H, br), 6.51-7.52(7H, m)    5-Cl        2', 4'-Cl             81-84                  C.sub.13 H.sub.8 Cl.sub.3 NO                         51.95  2.68  4.66                         (51.98 2.51  4.83)    5-Cl        2', 4'-OMe             102-103                  C.sub.15 H.sub.14 ClNO.sub.3                         61.76  4.84  4.80                         (61.79 4.88  4.72)    5-Cl        2', 6'-OMe             172  C.sub.15 H.sub.14 ClNO.sub.3                         61.76  4.84  4.80                         (61.54 4.72  4.87)    __________________________________________________________________________

                                      TABLE 75    __________________________________________________________________________                m.p            Elemental Analysis (Found)    X   Y       (°C.)                     Formula   C     H    N    __________________________________________________________________________    5-Cl        2',5'-OMe                oil  .sup.1 NMR(CDCL.sub.3)δ: 3.72(3H, s), 3.78(3H, s),                     6.39(2H, br s), 6.64                     (1H, d, J=8.6 Hz), 6.80(1H, d, J=2.6 Hz), 6.87-7.28(4H,                     m)    5-Cl        2',4',60'-OMe                188-189                     C.sub.16 H.sub.16 ClNO.sub.4                               59.73 5.01 4.35                               (59.93                                     5.00 4.30)    5-Cl        2', 3'-OCH.sub.2 O--                119-120                     C.sub.14 H.sub.10 ClNO.sub.3                               60.99 3.66 5.08                               (60.81                                     3.43 5.07)    5-Cl        3∝,40'-OCH.sub.2 O--                oil  .sup.1 NMR(CDCl.sub.3)δ: 6.06(2H, s), 6.67(1H, d),                     6.86(1H, d), 7.15-                     7.5(4H, m)    4-Cl        2'-Cl   112-113                     C.sub.13 H.sub.9 Cl.sub.2 NO                               58.67 3.41 5.26                               (58.47                                     3.45 5.16)    3,5-Cl        2'-OMe  88-90                     C.sub.14 H.sub.11 Cl.sub.2 NO                               60.02 3.96 5.00                               (59.96                                     3.85 4.96)    5-Cl        2',3'-OMe                91-92                     C.sub.15 H.sub.14 ClNO.sub.3                               61.76 4.84 4.80                               (61.59                                     4.87 4.79    __________________________________________________________________________

                                      TABLE 76    __________________________________________________________________________     ##STR228##                m.p.         Elemental Analysis (Found)    X      Y    (°C.)                     Formula C      H    N    __________________________________________________________________________    4,5-(CH.sub.2).sub.3           2'-Cl                oil          .sup.1 HNMR(CDCl.sub.3)δ: 1.8-2.1(2H, m),                             2.7-                             3.0(4H, m), 6.16(1H, s), 6.6-7.5(6H, m)    5-F    2'-Cl                77-79                     C.sub.13 H.sub.11 ClFNO                             62.04  4.41  5.57                             (62.10 4.40  5.57)    5-MeO  2'-Cl                oil          .sup.1 HNMR(CDCl.sub.3)δ: 3.67(3H, s),                             6.23(1H,                             br s), 6.50-6.54(7H, m)    5-Cl   2', 4'-Cl                104-106                     C.sub.13 H.sub.10 Cl.sub.3 NO +                             49.54  3.65  4.44                     0.7H.sub.2 O                             (49.59 3.48  4.34)    5-Cl   2', 4'-)Me                oil          .sup.1 HNMR(CDCl.sub.3)δ: 3.81(3H, s),                             3.85(3H, s)                             5.94(1H, s), 6.4-6.7(3H, m), 6.95-7.1(3H,    __________________________________________________________________________                             m)

                                      TABLE 77    __________________________________________________________________________                m.p            Elemental Analysis (Found)    X   Y       (°C.)                     Formula   C     H    N    __________________________________________________________________________    5-Cl        2',6'-OMe                130-135                     C.sub.15 H.sub.16 ClNO.sub.3                               61.33 5.49 4.77                               (61.26                                     5.46 4.71)    5-Cl        2',5'-OMe                177-178                     C.sub.15 H.sub.16 ClNO.sub.3                               61.33 5.49 4.77                               (61.22                                     5.54 4.72)    5-Cl        2',4',6'-OMe                163-164                     C.sub.15 H.sub.18 ClNO.sub.4                               59.35 5.60 4.33                               (59.57                                     5.63 4.39)    5-Cl        2',3'-OCH.sub.2 O--                119-120                     C.sub.14 H.sub.12 ClNO.sub.3                               60.55 4.36 5.04                               (60.49                                     4.20 5.10)    5-Cl        3',4'-OCH.sub.2 O--                136-137                     C.sub.14 H.sub.12 ClNO.sub.3                               60.55 4.36 5.04                               (60.41                                     4.48 4.96)    4-Cl        2'-Cl   oil  .sup.1 H-NMR(CDCl.sub.3)δ: 6.06(1H, s),                     6.55-6.75(3H, m),                     7.2-7.5(5H, m)    5-Cl        2',3'-OMe                124-126                     C.sub.15 H.sub.16 ClNO.sub.3                               61.33 5.49 4.77                               (61.25                                     5.58 4.66)    3,5-Cl        2'-OMe  84-86                     C.sub.14 H.sub.13 Cl.sub.2 NO.sub.2                               56.40 4.39 4.70                               (56.06                                     4.35 4.59)    H   2'-Cl   oil  .sup.1 H-NMR(CDCl.sub.3)δ: 5.30(1H, s), 6.17(1H,                     s), 6.5-7.6(7H, m)    __________________________________________________________________________

                                      TABLE 78    __________________________________________________________________________                m.p            Elemental Analysis (Found)    X   Y       (°C.)                     Formula   C     H    N    __________________________________________________________________________    5-CH.sub.3        2'-Cl   oil  .sup.1 H-NMR(CDCl.sub.3)δ: 2.17(3H, s), 6.16(1H,                     s), 6.6-7.6(7H, m)    5-Cl        2'-F    100-101                     C.sub.13 H.sub.11 ClFNO                               62.03 4.41 5.57                               (61.86                                     4.62 5.51)    H   2'-F    106-107                     C.sub.13 H.sub.12 FNO                               71.87 5.57 6.45                               (71.76                                     5.59 6.36)    H   2'-OMe  105-106                     C.sub.14 H.sub.15 NO.sub.2                               73.34 6.59 6.11                               (73.11                                     6.63 6.19)    5-Cl        2'-CF.sub.3                127-129                     C.sub.14 H.sub.11 ClF.sub.3 NO                               55.74 3.68 4.64                               (55.66                                     3.64 4.70)    5-Cl        2'-OMe  81-82                     C.sub.14 H.sub.14 ClNO.sub.2                               63.76 5.35 5.31                               (63.83                                     5.56 5.32)    5-Cl        2'-Br   87-88                     C.sub.13 H.sub.11 BrClNO                               49.95 3.55 4.48                               (50.03                                     3.71 4.44)    5-Br        2'-Cl   97-99                     C.sub.13 H.sub.11 BrClNO                               49.95 3.55 4.48                               (49.87                                     3.76 4.37)    6-Cl        4'-Cl   127-128                     C.sub.13 H.sub.11 Cl.sub.2 NO                               58.23 4.13 5.22                               (58.47                                     4.17 5.19)    __________________________________________________________________________

                                      TABLE 79    __________________________________________________________________________                m.p            Elemental Analysis (Found)    X   Y       (°C.)                     Formula   C     H    N    __________________________________________________________________________    H   2'-Me   110-111                     C.sub.14 H.sub.15 NO                               78.84 7.09 6.57                               (78.67                                     6.87 6.60)    5-Cl        3'-Cl   136-138                     C.sub.13 H.sub.11 Cl.sub.2 NO                               58.23 4.13 5.22                               (58.36                                     4.23 5.14)    5-CF.sub.3        H       86-87                     C.sub.14 H.sub.12 F.sub.3 NO                               62.92 4.53 5.24                               (62.84                                     4.55 5.11)    5-Cl        H       107-109                     C.sub.13 H.sub.12 ClNO                               66.81 5.18 5.99                               (66.80                                     5.19 5.97)    __________________________________________________________________________

                                      TABLE 80    __________________________________________________________________________     ##STR229##             m.p.        Elemental Analysis (Found)    X  Y     (°C.)                  Formula                         C      H     N    __________________________________________________________________________    5-Cl       2', 4'-OCH.sub.3             oil  C.sub.20 H.sub.26 ClNO.sub.3                         .sup.1 HNMR(CDCl.sub.3)δ: 0.92(9H, s,                         Bu.sup.1), 2.82                         (2H, s), 2.9-3.3(1H, br), 3.81(3H, s),                         3.86(3H, s), 4.6-5.0(1H, br), 5.92(1H, s),                         6.4-6.6(3H, m)6.95-7.2(3H, m)    5-Cl       2', 6'-OCH.sub.3             oil  C.sub.20 H.sub.26 ClNO.sub.3                         .sup.1 HNMR(CDCl.sub.3)δ: 1.06(9H, s),                         2.87(1H, d),                         J=11.4Hz), 2.96(1H, d, J=11.4Hz), 3.80(6H,                         s), 4.28, 5.61(each 1H, br) 6.26(1H, br),                         6.53(1H, d, J=2.6Hz), 6.60(1H, d,                         J=8.6Hz), 6.66(2H, d, J=8.4Hz), 7.09(1H, dd,                         J=2.4, 8.6Hz), 7.31(1H, t, J=8.4Hz)    5-Cl       2', 5'-OCH.sub.3             126-128                  C.sub.20 H.sub.26 ClNO.sub.3                         66.02  7.20  3.85                         (66.18 7.18  3.83)    __________________________________________________________________________

                                      TABLE 81    __________________________________________________________________________                m.p            Elemental Analysis (Found)    X   Y       (°C.)                     Formula   C     H    N    __________________________________________________________________________    5-Cl        2',4',6'-OCH.sub.3                150-151                     C.sub.21 H.sub.28 ClNO.sub.4                               64.03 7.16 3.56                               (64.19                                     7.00 3.48)    5-Cl        2',3'-OCH.sub.2 O--                     subjected to the next procedure without isolating    5-Cl        3',4'-OCh.sub.2 O--                oil  C.sub.19 H.sub.22 ClNO.sub.3                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.86(9H, s,                               Bu'), 2.75                               (2H, s), 5.67(1H, s), 5.95(2H, s), 6.5-7.3)                               (6H, m)    4-Cl        2'-Cl   oil  C.sub.18 H.sub.21 Cl.sub.2 NO                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.94(9H, s,                               Bu'), 2.84                               (2H, s), 6.12(1H, s), 6.5-7.5(7H, m)    3,5-Cl        2'-OCH.sub.3                oil  C.sub.19 H.sub.23 Cl.sub.2 NO.sub.2                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.98(9H, s,                               Bu'), 2.75                               (2H, s), 3.84(3H, s), 4.05(1H, br s), 6.28                               (1H, s), 6.9-7.4(6H, m)    5-Cl        2'OCH.sub.3                oil  C.sub.19 H.sub.24 ClNO.sub.2                               .sup.1 H-NMR(CDCl.sub.3)δ: 0.92(9H, s,                               Bu'), 2.83                               (2H, 2), 3.1-3.5(1H, br), 3.89(3H, s), 4.6-                     5.0(1H, br), 5.99(1H,s), 6.59(1H, d, J=8.8 Hz),                     6.9-7.4(6H, m)    5-Cl        2'-Br    99-100                     C.sub.18 H.sub.21 BrClNO                               56.49 5.53 3.66                               (56.69                                     5.50 3.42)    5-Br        2'-Cl   105-107                     C.sub.18 H.sub.21 BrClNO                               56.49 5.53 3.66                               (56.48                                     5.50 3.59)    5-Cl        2',3'-OMe                120-121                     C.sub.20 H.sub.26 ClNO.sub.3                               66.02 7.20 3.85                               (65.74                                     7.01 3.71)    __________________________________________________________________________

                                      TABLE 82    __________________________________________________________________________     ##STR230##             m.p.        Elemental Analysis (Found)    X   Y    (°C.)                  Formula                         C      H    N    __________________________________________________________________________    5-F 2'-Cl             84-86                  C.sub.17 H.sub.19 ClFNO                         66.34  6.22 4.55                         (66.21 6.22 4.50)    5-OCH.sub.3        2'-Cl             oil  C.sub.18 H.sub.22 ClNO.sub.2                         .sup.1 HNMR(CDCL.sub.3)δ: 0.85, 0.87(each 3H,                         each                         d, J=6.6Hz), 1.80(1H, m), 2.86(2H, d, J=6.6Hz),                         3.68(3H, s), 6.24(1H, s), 6.50-7.55(7H, m)    5-Cl        2', 4'-Cl             104-106                  C.sub.17 H.sub.18 Cl.sub.3 NO                         56.93  5.06 3.90                         (56.96 4.85 3.66)    5-Cl        2'-CF.sub.3             72-74                  C.sub.18 H.sub.19 ClF.sub.3 NO                         60.42  5.35 3.91                         (59.96 5.37 3.83)    5-Cl        2'-OCH.sub.3             oil  C.sub.18 H.sub.22 ClNO.sub.2                         .sup.1 HNMR(CDCl.sub.3)δ: 0.92(6H, d,                         J=6.6Hz),                         175-2.0(1H, m), 2.89(1H, d, J=6.8Hz), 3.1-                         3.4(1H, (Br, 3.88(3H, s), 4.7-5.1(1H, br),                         5.97(1H, s), 6.56(1H, d, J=8.82Hz), 6.9-                         7.4(6H, m)    __________________________________________________________________________

                                      TABLE 83    __________________________________________________________________________              m.p.         Elemental Analysis (Found)    X    Y    (°C.)                   Formula C       H      N    __________________________________________________________________________    5-Cl 2'-Br              96-98                   C.sub.17 H.sub.19 BrClNO                           55.38   5.19   3.80                           (55.55  5.20   3.74)    5-Br 2'-Cl              oil  C.sub.17 H.sub.19 BrClNO                           .sup.1 H-NMR (CDCl.sub.3) δ: 0.91(6H, d,                           J=6.6Hz), 1.7-                           2.0(1H, m), 2.89(2H, d, J=6.6Hz), 6.11(1H, s),                           6.53(1H, d, J=8.6Hz), 7.05(1H, d, J=2.4Hz),                           7.14-7.46(5H, m)    5-Cl 4'-Cl              oil  C.sub.17 H.sub.19 Cl.sub.2 NO                           .sup.1 H-NMR (CDCl.sub.3) δ: 0.828(3H, d,                           J=6.8Hz), 0.834                           (3H, d, J=6.8Hz), 1.64-1.86(1H, m), 2.2-2.8                           (1H, br), 2.80(2H, d, J=6.8Hz), 4.2-4.7(1H, br),                           5.73(1H, s), 6.54(1H, d, J=8.6Hz), 6.98(1H, d,                           J=2.4Hz), 7.14(1H, dd, J=8.6, 2.4Hz), 7.31(4H, s)    H    2'-CH.sub.3              oil  C.sub.18 H.sub.23 NO                           .sup.1 H-NMR (CDCl.sub.3) δ: 0.95(6H, d,                           J=6.6Hz), 1.8-                           2.0(1H, m), 2.21(3H, s), 2.94(2H, d, J=6.6Hz),                           5.98(1H, s), 6.5-6.8(2H, m), 7.1-7.35(3H, m),                           7.1-7.35(3H, m), 7.4-7.55(1H, m)    5-Cl 3'-Cl              73-74                   C.sub.17 H.sub.19 Cl.sub.2 NO                           62.97   5.91   4.32                           (62.81  5.88   4.19)    5-CF.sub.3         H    60-62                   C.sub.18 H.sub.20 F.sub.3 NO                           66.86   6.23   4.33                           (66.89  6.27   4.22)    5-Cl H    56-59                   C.sub.17 H.sub.20 ClNO                           70.46   6.96   4.83                           (70.45  7.11   4.90)    __________________________________________________________________________

                                      TABLE 84    __________________________________________________________________________     ##STR231##              m.p.         Elemental Analysis (Found)    X  Y      (°C.)                   Formula C      H     N    __________________________________________________________________________    5-Cl       2', 4'-OCH.sub.3              oil  C.sub.26 H.sub.32 ClNO.sub.6                           .sup.1 HNMR(CDCl.sub.3)δ: 0.82 and 0.93(9H,                           each s,                           Bu.sup.1), 1.22(3H, t, J=7.2Hz), 2.35-3.1(2H, m),                           3.65-3.9(6H, m), 4.0-4.5(3H, m), 5.9-                           6.55(5H, m), 6.75-7.9(4H, m)    5-Cl       2', 6'-OCH.sub.3              oil  C.sub.26 H.sub.32 NO.sub.6 Cl                           .sup.1 H-NMR(CDCl.sub.3)δ: 0.90, 0.95(9H,                           each s, Bu.sup.1),                           1.19-1.30(3H, m), 2.88-3.10(1H, m), 3.72-                           3.82(6H, m), 4.04-4.28(2H, m), 4.44-                           4.57(1H, m), 6.02-7.88(9H, m)    5-Cl       2', 5'-OCH.sub.3              140-142                   C.sub.26 H.sub.32 ClNO.sub.6                           63.73  6.58  2.86                           (63.67)                                  6.50  2.81)    5-Cl       2', 4', 6'-OCH.sub.3              oil  C.sub.27 H.sub.34 ClNO.sub.7                           .sup.1 HNMR(CDCl.sub.3)δ: 0.90 and 0.94(9H,                           each s,                           Bu.sup.1), 1.15-1.35(3H, m), 2.8-3.1(1H, m), 3.4-                           4.3(12H, m), 4.35-4.6(1H, m),                           5.9-6.45(5H, m), 6.8-7.95(3H, m)    __________________________________________________________________________

                                      TABLE 85    __________________________________________________________________________                 m.p.           Elemental Analysis (Found)    X    Y       (°C.)                       Formula  C       H      N    __________________________________________________________________________    5-Cl 2',3'-OCH.sub.2 O--                 oil   C.sub.25 H.sub.28 ClNO.sub.6                                .sup.1 H-NMR (CDCl.sub.3) δ: 0.92 and                                1.07(9H, each s,                                Bu.sup.t), 1.18-1.33(3H, m), 2.85-3.04(1H,                                m),                                4.05-4.34(2H, m), 4.46-4.54(1H, m), 5.87(2H,                                s),                                6.05-7.89(9H, m)    5-Cl 3',4'-OCH.sub.2 O--                 125-126                       C.sub.25 H.sub.28 ClNO.sub.6                                63.36   5.95   2.96                                (63.26  5.72   2.76)    4-Cl 2'-Cl   152-153                       C.sub.24 H.sub.27 Cl.sub.2 NO.sub.4                                62.07   5.86   3.02                                (61.78  5.93   2.88)    3,5-Cl         2'-OCH.sub.3                 162-164                       C.sub.25 H.sub.29 Cl.sub.2 NO.sub.5                                60.73   5.91   2.83                                (60.84  5.89   2.70)    5-Cl 2'-OCH.sub.3                 oil   C.sub.25 H.sub.30 ClNO.sub.5                                .sup.1 H-NMR (CDCl.sub.3) δ: 0.84 and                                0.93(9H, each s,                                Bu.sup.t), 1.15-1.3(2H, m), 2.5-3.2(2H, m),                                3.73                                and 3.82(3H, each s), 4.0-4.25(2H, m),                                4.25-4.6                                (1H, m), 6.0-6.5(3H, m), 6.7-7.85(7H, m)    5-Cl 2'-Br   168-169                       C.sub.24 H.sub.27 BrClNO.sub.4                                56.65   5.35   2.75                                (56.71  5.21   2.47)    5-Br 2'-Cl   171-174                       C.sub.24 H.sub.27 BrClNO.sub.4                                56.65   5.35   2.75                                (56.68  5.39   2.68)    5-Cl 2',3'-OCH.sub.3                 137-139                       C.sub.26 H.sub.32 ClNO.sub.6                                63.73   6.58   2.86                                (63.66  6.50   2.94)    __________________________________________________________________________

                                      TABLE 86    __________________________________________________________________________     ##STR232##             m.p.         Elemental Analysis (Found)    X   Y    (°C.)                  Formula C      H     N    __________________________________________________________________________    5-F 2'-Cl             148-151                  C.sub.23 H.sub.25 ClFNO.sub.4                          63.67  5.81  3.23                          (63.56 5.73  3.38)    5-OCH.sub.3        2'-Cl             oil  C.sub.24 H.sub.28 NO.sub.5 Cl                          .sup.1 HNMR(CDCl.sub.3)δ: 0.73-1.25(total 9H,                          m),                          1.78(1H, m), 2.35-3.10(2H, m), 3.70, 3.75                          (3H, each s), 4.10-4.38(4H, m),                          5.89-7.73(10H, m)    5-Cl        2', 4'-Cl             167-168                  C.sub.23 H.sub.24 Cl.sub.3 NO.sub.4                          56.98  4.99  2.89                          (56.85 4.84  2.63)    5-Cl        2'-CF.sub.3             164-165                  C.sub.24 H.sub.25 ClF.sub.3 NO.sub.4                          59.57  5.21  2.89                          (59.55 5.22  2.83)    5-Cl        2'-OCH.sub.3             oil  C.sub.24 H.sub.28 ClNO.sub.5                          .sup.1 HNMR(CDCl.sub.3)δ: 0.7-1.15(6H, m),                          1.15-                          1.4(3H, m), 1.6-2.1(1H, m), 2.4-3.1(2H, m),                          3.76 and 3.80(3H, each s), 4.0-                          4.45(4H, m), 5.9-6.45(3H, m),                          6.7-7.9(7H, m)    __________________________________________________________________________

                                      TABLE 87    __________________________________________________________________________              m.p.            Elemental Analysis (Found)    X    Y    (°C.)                     Formula  C       H      N    __________________________________________________________________________    5-Cl 2'-Br              158-160                     C.sub.23 H.sub.25 BrClNO.sub.4                              55.83   5.09   2.83                              (55.89  5.10   2.89)    5-Br 2'-Cl              157-159                     C.sub.23 H.sub.25 BrClNO.sub.4                              55.83   5.09   2.83                              (55.42  5.18   2.65)    5-Cl 4'-Cl              amorphous                     C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4 +                              60.85   5.64   3.09              solid  0.2H.sub.2 O                              (60.85  5.62   3.00)    H    2'-CH.sub.3              oil    C.sub.24 H.sub.29 NO.sub.4                              .sup.1 H-NMR (CDCl.sub.3) δ: 0.7-1.1(6H,                              m), 1.21(3H, t,                              J=7.0Hz), 1.5-2.0(1H, m), 2.29(3H, s), 2.0-                              2.3 and 2.9-3.1(1H, each m), 3.9-4.5(3H, m),                              5.9-6.4(2H, m), 6.6-6.9(1H, m), 6.95-7.9(8H,                              m)    5-Cl 3'-Cl              105-108                     C.sub.23 H.sub.25 Cl.sub.2 NO.sub.4                              61.34   5.60   3.11                              (61.37  5.53   3.08)    5-CF.sub.3         H    amorphous                     C.sub.24 H.sub.26 F.sub.3 NO.sub.4                              64.13   5.83   3.12              solid           (64.28  5.80   3.00)    5-Cl H    110-113                     C.sub.23 H.sub.26 ClNO.sub.4                              66.42   6.30   3.37                              (66.05  6.29   3.35)    __________________________________________________________________________

                  TABLE 88    ______________________________________     ##STR233##    m.p.                    Elemental Analysis (Found)    R      (°C.)                    Formula     C      H    N    ______________________________________     ##STR234##           101-103  C.sub.16 H.sub.10 Cl.sub.2 F.sub.5 NO.sub.2                                46.40 (46.28                                       2.43 2.42                                            3.38 3.47)           115-116    ______________________________________

Experimental Example 1

Assay Method of Squalene Synthetase Inhibitory Activity

The squalene synthetase inhibitory activity was assayed as follows withthe enzyme solutions described in the subsequent Experimental Examples1and 2.

More specifically, an enzyme solution (protein content 0.8 ug) preparedin Experimental Example 1or 2 was added to a solution (total volume 50ul)) containing 5 uM 1-³ H! farnesyl pyrophosphate (specific activity 25uCi/mole), 1 mM NADPH, 5 mM MgCl₂, 6 mM glutathione, a 100 mM buffersolution of potassium phosphate (pH 7.4) and a test drug (used as anaqueous solution or a DMSO solution), then the reaction was allowed toproceed at 37° C. for 45 minutes. To the reaction mixture was added 150ul of a mixture of chloroform and methanol (1:2) to suspend thereaction, followed by adding 50 ul of chloroform and 50 ul of a 3Naqueous solution of sodium hydroxide. 50 ul of the chloroform layer(lower layer) containing the reaction mixture having squalene as theprincipal component and 3 ml of toluene-based liquid scintillator weremixed, and its radioactivity was determined by means of a liquidscintillation counter.

The squalene synthetase inhibitory activity was expressed in terms ofthe concentration inhibiting by 50% the radioactivity taken into thechloroform layer (IC₅₀, molar concentration (M)).

Experimental Example 2

Preparation of rat-derived enzyme

An SD male rat (6 week old) was killed by bleeding, and its liver wasexcised. About 10 g of the liver was washed with a physiological salinesolution cooled with ice, which was then homogenized in 15 ml of anice-cooled buffer solution 100 mM potassium phosphate (pH 7.4), 15 mMnicotinamide, 2 mM MgCl₂ !, followed by centrifugation for 20 minutes(4° C.) with 10000 Xg. The supernatant layer was separated and subjectedto further centrifugation for 90 minutes (4° C.) with 105000 Xg. Thesediment was then suspended in an ice-cooled 100 mM phosphate buffersolution (pH 7.4), which was again subjected to centrifugation for 90minutes (4° C.) with 105000 Xg. The sediment thus obtained (microsomefraction) was suspended in an ice-cooled 100 mM potassium phosphatebuffer (pH 7.4) (about 40 mg/ml protein concentration, determined withBCA protein assay kit of Pias Co., Ltd.). This suspension was used asthe enzyme solution.

Experimental Example 3

Preparation of human-derived enzyme

Human hepatic carcinoma cells HepG2 (about 1×10⁹ cells) obtained byincubation on a Dulbecco-modified Eagle's medium (37° C. in the presenceof 5% CO₂) were suspended in 10 ml of an ice-cooled buffer solution 100mM potassium phosphate buffer (pH 7.4), 30 mM nicotinamide and 2.5 mMMgCl₂ !. The cells were crashed by means of ultrasonication (for 30seconds, twice). From the sonicate thus obtained, the microsome fractionwas obtained by the same procedure as in Experiment Example 1, which wassuspended in an ice-cooled 100 mM potassium phosphate buffer (pH 7.4)(about 4 mg/ml protein concentration). This suspension was used as theenzyme solution. The results are shown in Table 74.

                  TABLE 74    ______________________________________    Compd. No. Rat Enzyme (10.sup.-7 M)                             Man Enzyme (10.sup.-7 M)    ______________________________________    Ref. Ex.    5-1        83            68    2          47            51    3          40            38    4          63            64    7          5.4           7.1    8          5.3           --    12         2.3           --    W. Ex.    2-2        0.61          0.34    4          0.72          0.24    33-2       49            38    35-1       72            53    5          43            43    6          34            33    11         26            21    12         40            35    15         0.35          0.12    19         0.28          0.30    23         0.94          0.28    74-5       0.54          0.22    9          0.49          0.40    11         0.79          0.14    12         0.38          0.18    105        0.65          0.34    114        0.43          0.11    118 (1)    0.42          0.16    120        0.16          0.06    138        0.42          0.21    168        0.67          0.18    117        >100          --    ______________________________________

Experimental Example 4

Effects

The antifungal activities of the Compounds (I") were evaluated by thefollowing method: a sheet of filter paper disc (manufactured by ToyoSeisakusho, 8 mm in diameter) soaked in a 1000 μg/ml solution of acompound (I") in methanol was placed on an agar plate, which wasincubated at 28° C. for 2 days, and the diameter of the growthinhibition zone around the filter paper disc was measured. The followingculture media were used:

A: yeast nitrogen base agar medium (pH 7.0)

B: peptone-yeast extract-glucose agar medium (pH 7.0)

The antifungal spectra of the compound (I") are shown in Table 90.

The below mentioned test fungi are deposited at the Institute forFermentation, Osaka, Japan (IFO). Their accession numbers are shown inTable 90.

                  TABLE 90    ______________________________________    Antifungal spectra                   Inhibition zone diameter                   (mm)                         Example  Example                                         Example    Test fungi  Media    75-7     75-6   74-10    ______________________________________    Candida albicans                A        16       14     18    IFO 0583    Aspergillus niger                A        30       24     0    IFO 4066    Cryptococcus                A        19       13     14    neoformans    IFO 0410    Trichophyton rubrum                B        16       13     20    IFO 6467    Trichophyton                B        12       12     12    mentagrophytes    IFO 7522    Microsporum gypseum                B        13       12     13    IFO 6076    ______________________________________

Experimental Example 5

In vivo cholesterogenesis in the liver

Six-week-old, male Sprague-Dawley rats were given 5%-cholestylamine as adietary admixture for 4 days. They were administered compound at a doseof 30 mg/kg as a suspension of 0.5%-methylcellulose solution and wereintravenously given 2 uCi of ¹⁴ C!acetate 1 hour after theadministration. One hour later, rats were sacrificed and livers wereremoved. Hepatic sterols were extracted with petroleum ether aftersaponification, and the radioactivity of digitonin-precipitable fractionwas measured. Example 1-(4) inhibited the hepatic cholesterogenesis by38% compared to the control group given only 5%-methylcellulosesolution.

Formulation Examples

A squalene synthetase inhibiting agents containing, as its effectivecomponent, a 4,1-benzoxazepine-2-one derivative shown by the formula (I)of this invention or a salt thereof, in the case where it is used as atherapeutic agent of hypercholesteremia, can be formulated in accordancewith, for example, the following prescriptions.

1. Capsules

(1) Compound obtained in Example 28-19 10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) were blended and the mixture wasgranulated, to which was added the balance of (4). The mixture wasfilled in a gelatin capsule.

2. Tablets

(1) Compound obtained in Example 28-19 10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) were blendedand the mixture was granulated, to which were added the balance of (4)and (5). The mixture was subjected to compression-molding to providetablets.

3. Injections

(1) Sodium salt of the compound obtained in Example 28-19 10 mg

(2) Inositol 100 mg

(3) Benzyl alcohol 20 mg

One ampoule 130 mg

(1), (2) and (3) were dissolved in distilled water for injection to makethe whole volume 2 ml, which was put in an ampoule, and the ampoule wassealed. All the processes were conducted under sterilized conditions.

4. Capsules

(1) Compound obtained in Example 1-4 10 mg

(2) Lactose 90 mg

(3) Microcrystalline cellulose 70 mg

(4) Magnesium stearate 10 mg

One capsule 180 mg

(1), (2) and (3) and one half of (4) were blended and the mixture wasgranulated, to which was added the balance of (4). The mixture wasfilled in a gelatin capsule.

5. Tablets

(1) Compound obtained in Example 1-4 10 mg

(2) Lactose 35 mg

(3) Corn starch 150 mg

(4) Microcrystalline cellulose 30 mg

(5) Magnesium stearate 5 mg

One tablet 230 mg

(1), (2) and (3) and two thirds of (4) and one half of (5) were blendedand the mixture was granulated, to which were added the balance of (4)and (5). The mixture was subjected to compression-molding to providetablets.

6. Injections

(1) Sodium salt of the compound obtained in Example 1-4 10 mg

(2) Inositol 100 mg

(3) Benzyl alcohol 20 mg

One ampoule 130 mg

(1), (2) and (3) were dissolved in distilled water for injection to makethe whole volume 2 ml, which was put in an ampoule, and the ampoule wassealed. All the processes were conducted under sterilized conditions.

What is claimed is:
 1. A method for the prophylaxis or treatment ofhyperlipidemia in a mammal in need thereof by administering to saidmammal a pharmaceutically effective amount of a compound represented bythe formula (Ir), ##STR235## wherein R₁ is hydrogen or an optionallysubstituted hydrocarbon group; R₂ and R₃ independently is hydrogen, anoptionally substituted alkyl group, an optionally substituted phenylgroup or an optionally substituted aromatic heterocyclic ring group; X'is a substituent comprising an optionally esterified carboxyl group, anoptionally substituted carbamoyl group, an optionally substitutedhydroxyl group, an optionally substituted amino group or an optionallysubstituted heterocyclic radical having a protonizable hydrogen; Ring Ais an optionally substituted benzene ring; Ring J' is a 7- to 8-memberedheterocyclic ring containing at most three ring constituting heteroatoms; the Ring J' optionally having, besides R₁ R₂, R₃ and X', afurther substituent selected from the group consisting of a C₁₋₆straight-chain or branched alkyl group, acyl group, oxo, thioxo, anoptionally substituted hydroxyl group, and an optionally substitutedamino group, wherein the alkyl and acyl groups may optionally have fromone to five halogen atoms,the condensed ring comprising Ring A and RingJ' is selected from the group consisting of ##STR236## or apharmaceutically acceptable salt thereof.
 2. The method as claimed inclaim 1, in which R₁ is an aliphatic chain hydrocarbon group.
 3. Themethod as claimed in claim 2, in which R₁ is an alkyl group.
 4. Themethod as claimed in claim 1, in which R₂ or R₃ is an optionallysubstituted phenyl group.
 5. The method as claimed in claim 1, in whichX' is an alkyl substituted with an optionally esterified carboxyl group.6. The method as claimed in claim 1, in which X' is an alkyl substitutedwith an optionally substituted heterocyclic radical having aprotonizable hydrogen.
 7. The method as claimed in claim 6, in which theheterocyclic radical is ##STR237##
 8. The method as claimed in claim 5,wherein the alkyl is a straight-chain C₁₋₄ alkyl.
 9. The method asclaimed in claim 1, in which the further substituent of Ring J' is oxoor thioxo.
 10. The method as claimed in claim 1, in which the compoundis represented by the formula (Ir') ##STR238## wherein R₁ is hydrogen ofan optionally substituted hydrocarbon group; R₂ and R₃ independently ishydrogen, an optionally substituted alkyl group, an optionallysubstituted phenyl group or an optionally substituted aromaticheterocyclic ring group; X₁ is a bond or a divalent chain having 1 to 7atoms; Y is an optionally esterified carboxyl group, an optionallysubstituted carbamoyl group, an optionally substituted hydroxyl group,an optionally substituted amino group or an optionally substitutedheterocyclic radical having protonizable hydrogen; Ring B is anoptionally substituted benzene ring, or a pharmaceutically acceptablesalt thereof.
 11. The method as claimed in claim 10, in which R₁ is analiphatic chain hydrocarbon group.
 12. The method as claimed in claim11, in which R₁ is an alkyl group.
 13. The method as claimed in claim10, in which R₂ or R₃ is an optionally substituted phenyl group.
 14. Themethod as claimed in claim 10, in which X₁ is a straight or branchedalkylene chain.
 15. The method as claimed in claim 14, in which X₁ is astraight C₁₋₄ alkylene chain.
 16. The method as claimed in claim 10, inwhich Y is an optionally esterified carboxyl group.
 17. The method asclaimed in claim 10, in which Y is an optionally substitutedheterocyclic radical having a protonizable hydrogen.
 18. The method asclaimed in claim 17, in which the heterocyclic radical is ##STR239## 19.The method as claimed in claim 1, in which the compound is(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid or a pharmaceutically acceptable salt thereof.
 20. The method asclaimed in claim 1, in which the compound is(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid or a pharmaceutically acceptable salt thereof.
 21. The method asclaimed in claim 1, in which the compound is(3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid or a pharmaceutically acceptable salt thereof.
 22. The method asclaimed in claim 19, in which the salt is a sodium salt.
 23. The methodas claimed in claim 20, in which the salt is a sodium salt.
 24. Themethod as claimed in claim 21, in which the salt is a sodium salt.
 25. Amethod for the prophylaxis or treatment of hypertriglyceridemia in amammal in need thereof by administering to said mammal apharmaceutically effective amount of a compound represented by theformula (Ir) ##STR240## wherein R₁ is hydrogen or an optionallysubstituted hydrocarbon group; R₂ and R₃ independently is hydrogen, anoptionally substituted alkyl group, an optionally substituted phenylgroup or an optionally substituted aromatic heterocyclic ring group; X'is a substituent comprising an optionally esterified carboxyl group, anoptionally substituted carbamoyl group, an optionally substitutedhydroxyl group, an optionally substituted amino group or an optionallysubstituted heterocyclic radical having a protonizable hydrogen; Ring Ais an optionally substituted benzene ring; Ring J' is a 7- to 8-memberedheterocyclic ring containing at most three ring constituting heteroatoms; the Ring J' optionally having, besides R₁, R₂, R₃ and X', afurther substituent selected from the group consisting of C₁₋₆straight-chain or branched alkyl group acyl group, oxo, thioxo, anoptionally substituted hydroxyl group and an optionally substitutedamino group, wherein the alkyl and acyl groups may optionally have oneto five halogen atoms,the condensed ring comprising Ring A and Ring J'is ##STR241## or a pharmaceutically acceptable salt thereof.
 26. Amethod for the prophylaxis or treatment of hyperlipidemia in a mammal inneed thereof by administering to said mammal a pharmaceuticallyeffective amount of a compound represented by the formula (Ir),##STR242## wherein R₁ is hydrogen or an optionally substitutedhydrocarbon group; R₂ and R₃ independently is hydrogen, an optionallysubstituted alkyl group, an optionally substituted phenyl group or anoptionally substituted aromatic heterocyclic ring group; X' is asubstituent comprising an optionally esterified carboxyl group, anoptionally substituted carbamoyl group, an optionally substitutedhydroxyl group, an optionally substituted amino group or an optionallysubstituted heterocyclic radical having a protonizable hydrogen; Ring Ais an optionally substituted aromatic heterocyclic ring; Ring J' is a 7-to 8-membered heterocyclic ring containing at most three ringconstituting hetero atoms; the Ring J' optionally having, besides R₁,R₂, R₃, and X', a further substituent selected from the group consistingof C₁₋₆ straight-chain or branched alkyl group, acyl group, oxo, thioxo,an optionally substituted hydroxyl group and an optionally substitutedamino group, wherein the alkyl and acyl groups may optionally have oneto five halogen atoms,or a pharmaceutically acceptable salt thereof. 27.The method as claimed in claim 26, in which R₁ is an aliphatic chainhydrocarbon group.
 28. The method as claimed in claim 27, in which R₁ isan alkyl group.
 29. The method as claimed in claim 26, in which R₂ or R₃is an optionally substituted phenyl group.
 30. The method as claimed inclaim 26, in which X' is an alkyl substituted with an optionallyesterified carboxyl group.
 31. The method as claimed in claim 26, inwhich X' is an alkyl substituted with an optionally substitutedheterocyclic radical having a protonizable hydrogen.
 32. The method asclaimed in claim 31, in which the heterocyclic radical is ##STR243## 33.The method as claimed in claim 30, wherein the alkyl is a straight-chainC₁₋₄ alkyl.
 34. The method as claimed in claim 26, in which the aromaticheterocyclic ring represented by the Ring A is ##STR244##
 35. The methodas claimed in claim 26, in which the further substituent of Ring J' isoxo or thioxo.
 36. The method as claimed in claim 26, in which thecondensed ring comprising Ring A and Ring J' is ##STR245##
 37. A methodfor the prophylaxis or treatment of hypertriglyceridemia in a mammal inneed thereof by administering to said mammal a pharmaceuticallyeffective amount of a compound represented by the formula (Ir)##STR246## wherein R₁ is hydrogen or an optionally substitutedhydrocarbon group; R₂ and R₃ independently is hydrogen, an optionallysubstituted alkyl group, an optionally substituted phenyl group or anoptionally substituted aromatic heterocyclic ring group; X' is asubstituent comprising an optionally esterified carboxyl group, anoptionally substituted carbamoyl group, an optionally substitutedhydroxyl group, an optionally substituted amino group or an optionallysubstituted heterocyclic radical having a protonizable hydrogen; Ring Ais an optionally substituted aromatic heterocyclic ring; Ring J' is a 7-to 8-membered heterocyclic ring containing at most three ringconstituting hetero atoms; the Ring J' optionally having, besides R₁,R₂, R₃, and X', a further substituent selected from the group consistingof C₁₋₆ straight-chain or branched alkyl group, acyl group, oxo, thioxo,an optionally substituted hydroxyl group and an optionally substitutedamino group, wherein the alkyl and acyl group may optionally have fromone to five halogen atoms,or a pharmaceutically acceptable salt thereof.38. A method for the prophylaxis or treatment of hyperlipidemia in amammal in need thereof comprising administering to said mammal apharmaceutically acceptable amount of a compound of the formula##STR247## wherein R₁ is (i) hydrogen,(ii) a C₁₋₇ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, (iii) a C₃₋₉ cycloalkyl group, acycloalkenyl group selected from among 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,1-cyclobuten-1-yl and 1-cyclopenten-1-yl, a cycloalkadienyl groupselected from among 2,4-cyclopentadien-1-yl, 2,4 cyclohexadien-1-yl, and2,5-cyclohexadien-1-yl, or (iv) an aryl group selected from amongphenyl, naphthyl, anthryl, phenanthryl and acenaphythylenyl in whicheach of the group of (ii), (iii) and (iv) is unsubstituted orsubstituted with 1 to 5 substituent(s) selected from the groupconsisting of(1) phenyl, naphthyl, anthryl, phenanthryl,acenaphthylenyl, C₃₋₇ cycloalkyl groups and C₃₋₆ cycloalkenyl groupseach of which is unsubstituted or substituted with 1 to 2 substituent(s)selected from among C₁₋₃ alkoxy groups and C₁₋₃ alkyl groups, (2) furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, alpha-carbolinyl, beta-carbolinyl,tau-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, 1,2,4-triazolo4,3-b!pyridazinyl, oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl or piperazinyl, each of said groups beingunsubstituted or substituted with C₁₋₃ alkyl, (3) amino groups, hydroxylgroups and thiol groups each of which is unsubstituted or substitutedwith C₁₋₃ alkyl groups and (4) halogen atoms; and having each of thegroups of (iii) and (iv) may further have a C₁₋₃ alkyl group, and (5)C₁₋₆ acyl groups; each of R₂ and R₃ is independently (i) hydrogen; (ii)a C₁₋₆ alkyl group unsubstituted or substituted with substituent(s)selected from among halogens and C₁₋₄ alkoxy groups; (iii) a phenylgroup unsubstituted or substituted by 1 to 3 substituent(s) selectedfrom among (1) halogen atoms, (2) C₁₋₄ alkyl groups unsubstituted orsubstituted with 1 to 3 halogen atoms, (3) C₁₋₄ alkoxy groupsunsubstituted or substituted with 1 to 3 halogen atoms, (4) hydroxylgroups unsubstituted or substituted with a C₁₋₄ alkyl group, a C₃₋₆cycloalkyl group, phenyl, 1-naphthyl, 2-naphthyl, benzyl or phenethyl,(5) nitro group and (6) cyano group in which the two adjoiningsubstituents on the phenyl group may cooperate therewith to form a ringwhich is unsubstituted or substituted with a C₁₋₃ alkyl or (iv) furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,π-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridiyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl,imidazo 1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl or1,2,4-triazolo 4,3-b!pyridazinyl, each of said groups beingunsubstituted or substituted with C₁₋₃ alkyl; X is a bond or a divalentchain represented by the formula ##STR248## wherein m and n denoteindependently 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfuratom, sulfoxide, sulfone, ##STR249## wherein R₆ and R₇ independentlystand for (i) hydrogen atom; (ii) a C₁₋₆ alkyl group unsubstituted orsubstituted with furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl,indolyl, imidazolyl, isoindolyl, an amino group unsubstituted orsubstituted with C₁₋₃ alkyl group(s), a hydroxyl group unsubstituted orsubstituted with a C₁₋₃ alkyl group, a thiol group unsubstituted orsubstituted with a C₁₋₃ alkyl group, carboxyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-naphtoxycarbonyl or2-naphtoxycarbonyl or a halogen atom; (iii) benzyl, naphthylmethyl,phenylethyl, phenylpropyl or phenylbutyl unsubstituted or substitutedwith substituent(s) selected from halogens, C₁₋₃ alkoxy groups, hydroxylgroup, amino group, carboxyl group and sulfhydryl or (iv) a phenyl groupunsubstituted or substituted with substituent(s) selected from halogenatoms and C₁₋₃ alkyl groups; R₅ stands for hydrogen atom, a C₁₋₄ alkyl,a C₇₋₁₅ aralkyl, a lower alkanoyl group, a lower alkenoyl group, a loweralkanesulfonyl group, benzoyl, p-toluoyl, 1-naphthoyl and 2-naphthoyl,phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl cinnamoyl,atropoyl, benzenesulfonyl or p-toluenesulfonyl; Y is (i) (a) carboxylgroup, (b) a lower alkoxy (thio) carbonyl group having optionally one ormore substituent(s) selected from among(1) hydroxyl groups unsubstitutedor substituted with a lower alkanoyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl orcyclohexyloxycarbonyl, (2) C₁₋₄ alkoxy carbonyl groups, (3) carbamoylgroups unsubstituted or substituted with substituent(s) selected fromamong C₁₋₃ alkyl groups, C₃₋₆ cycloalkyl groups, phenyl group, benzylgroup, carboxyl group, methoxycarbonyl, ethoxycarbonyl, andpropoxycarbonyl, (4) phenyl and C₃₋₆ cycloalkyl groups, each of which isunsubstituted or substituted with substituent(s) selected from amongC₁₋₃ alkyl groups and C₁₋₃ alkoxy groups, (5) C₁₋₃ alkenyl groups, (6)5-membered heterocyclic groups having one to three oxygen atoms, whichmay have one or more substituent(s) selected from the group consistingof C₁₋₃ alkyl and oxo, or a fused ring formed by cooperating said5-membered heterocyclic group with a benzene ring, or (c)phenoxy(thio)carbonyl, 1-naphtoxy(thio)carbonyl or benzyloxy(thio)carbonyl; (ii) a hydroxyl group unsubstituted or substituted with (1) aC₁₋₄ alkyl group, (2) a C₃₋₆ cycloalkyl group, (3) a phenyl, 1-naphthyl,2-naphthyl, benzyl or phenethyl group each of which is unsubstituted orsubstituted with halogen atom(s) or carboxyl group(s) optionallyesterified with C₁₋₄ alkyl; (iii) an amino group, unsubstituted orsubstituted with (1) C₁₋₄ alkyl group(s), (2) C₃₋₆ cycloalkyl(s) or (3)phenyl, 1-naphthyl, 2-naphthyl, benzyl and phenethyl group(s) each ofwhich is unsubstituted or substituted with substituent(s) selected fromamong halogen atoms and carboxyl groups optionally esterified with C₁₋₄alkyl group in which the two substituents on the nitrogen atom may form,taken together with the nitrogen atom, a cyclic amino group; (iv) aphenyl group unsubstituted or substituted with substituents selectedfrom among (1) C₁₋₄ alkyl groups unsubstituted or substituted withsubstituent(s) selected from carboxyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl and sec-butoxycarbonyl,(2) C₁₋₄ alkoxy groups, (3)methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl and sec-butoxycarbonyl, (4) phenylgroups unsubstituted or substituted with substituent(s) selected fromcarboxyl group, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl andsec-butoxycarbonyl, (5) amino groups unsubstituted or substituted withC₁₋₃ alkyl group(s) and (6) tetrazol-5-yl,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl and2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl; (v) a carbamoyl groupunsubstituted or substituted with 1 to 2 substituent(s) selected fromamong(1) C₁₋₆ alkyl groups and C₃₋₆ cycloalkyl groups each of which isunsubstituted or substituted with 1 to 3 substituent(s) selected fromamong carboxyl groups optionally esterified the C₁₋₅ alkyl group, furyl,thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl,amino group, hydroxyl group and phenyl group, (2) aryl groups andaralkyl groups unsubstituted or substituted with substituent(s) selectedfrom among halogen atoms and carboxyl groups optionally esterified withC₁₋₄ alkyl groups, in which the two substituents on the nitrogen atommay form a cyclic amino group taken together with the nitrogen atom; or(vi) tetrazol-5-yl or a group represented by the formula ##STR250##wherein i stands for --O-- or --S--; j stands for ##STR251## providedthat, when X is methylene and R₁ is not an alkyl group having more than4 carbon atoms, Y is neither carboxyl group nor alkoxycarbonyl group;the ring A being optionally substituted by C₁₋₄ alkoxy or a halogenatom, or a pharmaceutically acceptable salt thereof.
 39. A method forthe prophylaxis or treatment of hyperlipidemia in a mammal in needthereof comprising administering to said mammal a pharmaceuticallyacceptable amount of a compound of formula (I') ##STR252## wherein R₁ is(i) hydrogen, (ii) a C₁₋₇ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group,(iii) a C₃₋₉ cycloalkyl group, a cycloalkenyl groupselected from among 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and1-cyclopenten-1-yl, a cycloalkadienyl group selected from among2,4-cyclopentadien-1-yl, 2,4 cyclohexadien-1-yl, and2,5-cyclohexadien-1-yl, or (iv) an aryl group selected from amongphenyl, naphthyl, anthryl, phenanthryl and acenaphythylenyl in whicheach of the group of (ii), (iii) and (iv) is unsubstituted orsubstituted with 1 to 5 substituent(s) selected from the groupconsisting of(1) phenyl, naphthyl, anthyl, phenanthryl, acenaphthylenyl,C₃₋₇ cycloalkyl groups and C₃₋₆ cycloalkenyl groups each of which isunsubstituted or substituted with 1 to 2 substituent(s) selected fromamong C₁₋₃ alkoxy groups and C₁₋₃ alkyl groups, (2) furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzob!thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,τ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxthinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, 1,2,4-triazolo4,3-b!pyridazinyl, oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl or piperazinyl, each of said groups beingunsubstituted or substituted with C₁₋₃ alkyl, (3) amino groups, hydroxylgroups and thiol groups each of which is unsubstituted or substitutedwith C₁₋₃ alkyl groups and (4) halogen atoms; and having each of thegroups of (iii) and (iv) may further have a C₁₋₃ alkyl group, and (5)C₁₋₆ acyl groups; each of R₂ and R₃ is independently (i) hydrogen; (ii)a C₁₋₆ alkyl group unsubstituted or substituted with substituent(s)selected from among halogens and C₁₋₄ alkoxy groups; (iii) a phenylgroup unsubstituted or substituted by 1 to 3 substituent(s) selectedfrom among (1) halogen atoms, (2) C₁₋₄ alkyl groups unsubstituted orsubstituted with 1 to 3 halogen atoms, (3) C₁₋₄ alkoxy groupsunsubstituted or substituted with 1 to 3 halogen atoms, (4) hydroxylgroups unsubstituted or substituted with a C₁₋₄ alkyl group, a C₃₋₆cycloalkyl group, phenyl, 1-naphthyl, 2-naphthyl, benzyl or phenethyl,(5) nitro group and (6) cyano group in which the two adjoiningsubstituents on the phenyl group may cooperate therewith to form a ringwhich is unsubstituted or substituted with a C₁₋₃ alkyl or (iv) furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,π-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl or 1,2,4-triazolo4,3-b!pyridazinyl, each of said groups being unsubstituted orsubstituted with C₁₋₃ alkyl; X is a bond or a divalent chain representedby the formula ##STR253## wherein m and n denote independently 0, 1, 2or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide,sulfone, ##STR254## wherein R₆ and R₇ independently stand for (i)hydrogen atoms (ii) a C₁₋₆ alkyl group unsubstituted or substituted withfuryl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl,isoindolyl, an amino group unsubstituted or substituted with C₁₋₃ alkylgroup(s), a hydroxyl group unsubstituted or substituted with a C₁₋₃alkyl group, a thiol group unsubstituted or substituted with a C₁₋₃alkyl group, carboxyl group, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, phenoxycarbonyl, 1-naphtoxycarbonyl or2-naphtoxycarbonyl or a halogen atom; (iii) benzyl, napthylmethyl,phenylethyl, phenylpropyl or phenylbutyl unsubstituted or substitutedwith substituent(s) selected from halogens, C₁₋₃ alkoxy groups, hydroxylgroup, amino group, carboxyl group and sulfhydryl or (iv) a phenyl groupunsubstituted or substituted with substituent(s) selected from halogenatoms and C₁₋₃ allyl groups; R₅ stand for hydrogen atom, a C₁₋₄ alkyl, aC₇₋₁₅ aralkyl, a lower alkanoyl group, a lower alkenoyl group, a loweralkanesulfonyl group, benzoyl, p-toluoyl, 1-naphthoyl and 2-naphthoyl,phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl cinnamoyl,atropoyl, benzenesulfonyl or p-toluenesulfonyl; Y is (i) (a) carboxylgroup, (b) a lower alkoxy (thio) carbonyl group having optionally one ormore substituent(s) selected from among(1) hydroxyl groups unsubstitutedor substituted with a lower alkanoyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl orcyclohexyloxycarbonyl, (2) C₁₋₄ alkoxy carbonyl groups, (3) carbamoylgroups unsubstituted or substituted with substituent(s) selected fromamong C₁₋₃ alkyl groups, C₃₋₆ cycloalkyl groups, phenyl group, benzylgroup, carboxyl group, methoxycarbonyl and ethoxycarbonyl,propoxycarbonyl, (4) phenyl and C₃₋₆ cycloalkyl groups each of which isunsubstituted or substituted with substituent(s) selected from amongC₁₋₃ alkyl groups and C₁₋₃ alkoxy groups, (5) C₁₋₃ alkenyl groups, (6)5-membered heterocyclic groups having one to three oxygen atoms, whichmay have one or more substituent(s) selected from the group consistingof C₁₋₃ alkyl and oxo, or a fused ring formed by cooperating said5-membered heterocyclic group with a benzene ring, or (c)phenoxy(thio)carbonyl, 1-naphtoxy(thio)carbonyl or benzyloxy (thio)carbonyl; (ii) a hydroxyl group unsubstituted or substituted with (1) aC₁₋₄ alkyl group, (2) a C₃₋₆ cycloalkyl group, (3) a phenyl, 1-naphthyl,2-naphthyl, benzyl or phenethyl group each of which is unsubstituted orsubstituted with halogen atom(s) or carboxyl group(s) optionallyesterified with C₁₋₄ alkyl; (iii) an amino group, unsubstituted orsubstituted with (1) C₁₋₄ alkyl group(s), (2) C₃₋₆ cycloalkyl(s) or (3)phenyl, 1-naphthyl, 2-naphthyl, benzyl and phenethyl group(s) each ofwhich is unsubstituted or substituted with substituent(s) selected fromamong halogen atoms and carboxyl groups optionally esterified with C₁₋₄alkyl group in which the two substituents on the nitrogen atom may form,taken together with the nitrogen atom, a cyclic amino group; (iv) aphenyl group unsubstituted or substituted with substituents selectedfrom among (1) C₁₋₄ alkyl groups unsubstituted or substituted withsubstituent(s) selected from carboxyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl and sec-butoxycarbonyl,(2) C₁₋₄ alkoxy groups, (3)methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl and sec-butoxycarbonyl, (4) phenylgroups unsubstituted or substituted with substituent(s) selected fromcarboxyl group, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl andsec-butoxycarbonyl, (5) amino groups unsubstituted or substituted withC₁₋₃ alkyl group(s) and (6) tetrazol-5-yl,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl and2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl; (v) a carbamoyl groupunsubstituted or substituted with 1 to 2 substituent(s) selected fromamong (1) C₁₋₆ alkyl groups and C₃₋₈ cycloalkyl groups each of which isunsubstituted or substituted with 1 to 3 substituent(s) selected fromamong carboxyl groups optionally esterified the C₁₋₅ alkyl group, furyl,thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl,amino group, hydroxyl group and phenyl group,(2) aryl groups and aralkylgroups unsubstituted or substituted with substituent(s) selected fromamong halogen atoms and carboxyl groups optionally esterified with C₁₋₄alkyl groups, in which the two substituents on the nitrogen atom mayform a cyclic amino group taken together with the nitrogen atom; or (vi)tetrazol-5-yl or a group represented by the ##STR255## wherein i standsfor --O-- or --S--; j stands for ##STR256## provided that, when X ismethylene, Y is neither carboxyl group nor alkoxycarbonyl group; thering A being optionally be substituted by C₁₋₄ alkoxy or a halogen atom,or a pharmaceutically acceptable salt thereof.
 40. A method for theprophylaxis or treatment of hypertriglyceridemia in a mammal in needthereof comprising administering to said mammal a pharmaceuticallyacceptable amount of a compound of the formula ##STR257## wherein R₁ is(i) hydrogen,(ii) a C₁₋₇ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, (iii) a C sub 3-9 cycloalkyl group, a cycloalkenyl groupselected from among 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and1-cyclopenten-1-yl, a cycloalkadienyl group selected from among2,4-cyclopentadien-1-yl, 2,4 cyclohexadien-1-yl, and2,5-cyclohexadien-1-yl, or (iv) an aryl group selected from amongphenyl, naphthyl, anthryl, phenanthryl and acenaphythylenyl in whicheach of the group of (ii), (iii) and (iv) is unsubstituted orsubstituted with 1 to 5 substituent(s) selected from the groupconsisting of(1) phenyl, naphthyl, anthryl, phenanthryl,acenaphthylenyl, C₃₋₇ cycloalkyl groups and C₃₋₆ cycloalkenyl groupseach of which is unsubstituted or substituted with 1 to 2 substituent(s)selected from among C₁₋₃ alkoxy groups and C₁₋₃ alkyl groups, (2) furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,π-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, 1,2,4-triazolo4,3-b!pyridazinyl, oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl or piperazinyl, each of said groups beingunsubstituted or substituted with C₁₋₃ alkyl, (3) amino groups, hydroxylgroups and thiol groups each of which is unsubstituted or substitutedwith C₁₋₃ alkyl groups and (4) halogen atoms; and having each of thegroups of (iii) and (iv) may further have a C₁₋₃ alkyl group, and (5)C₁₋₆ acyl groups; each of R₂ and R₃ is independently (i) hydrogen; (ii)a C₁₋₆ alkyl group unsubstituted or substituted with substituent(s)selected from among halogens and C₁₋₄ alkoxy groups; (iii) a phenylgroup unsubstituted or substituted by 1 to 3 substituent(s) selectedfrom among (1) halogen atoms, (2) C₁₋₄ alkyl groups unsubstituted orsubstituted with 1 to 3 halogen atoms, (3) C₁₋₄ alkoxy groupsunsubstituted or substituted with 1 to 3 halogen atoms, (4) hydroxylgroups unsubstituted or substituted with a C₁₋₄ alkyl group, a C₃₋₆cycloalkyl group, phenyl, 1-naphthyl, 2-naphthyl, benzyl or phenethyl,(5) nitro group and (6) cyano group in which the two adjoiningsubstituents on the phenyl group may cooperate therewith to form a ringwhich is unsubstituted or substituted with a C₁₋₃ alkyl or (iv) furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,π-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridiyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl,imidazo 1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl or1,2,4-triazolo 4,3-b!pyridazinyl, each of said groups beingunsubstituted or substituted with C₁₋₃ alkyl; X is a bond or a divalentchain represented by the formula ##STR258## wherein m and n denoteindependently 0, 1, 2 or 3; E stands for a bond or oxygen atom, sulfuratom, sulfoxide, sulfone, ##STR259## wherein R₆ and R₇ independentlystand for (i) hydrogen atom; (ii) a C₁₋₆ alkyl group unsubstituted orsubstituted with furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl,indolyl, imidazolyl, isoindolyl, an amino group unsubstituted orsubstituted with C₁₋₃ alkyl group(s), a hydroxyl group unsubstituted orsubstituted with a C₁₋₃ alkyl group, a thiol group unsubstituted orsubstituted with a C₁₋₃ alkyl group, carboxyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-naphtoxycarbonyl or2-naphtoxycarbonyl or a halogen atom; (iii) benzyl, naphthylmethyl,phenylethyl, phenylpropyl or phenylbutyl unsubstituted or substitutedwith substituent(s) selected from halogens, C₁₋₃ alkoxy groups, hydroxylgroup, amino group, carboxyl group and sulfhydryl or (iv) a phenyl groupunsubstituted or substituted with substituent(s) selected from halogenatoms and C₁₋₃ alkyl groups; R₅ stands for hydrogen atom, a C₁₋₄ alkyl,a C₇₋₁₅ aralkyl, a lower alkanoyl group, a lower alkenoyl group, a loweralkanesulfonyl group, benzoyl, p-toluoyl, 1-naphthoyl and 2-naphthoyl,phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl cinnamoyl,atropoyl, benzenesulfonyl or p-toluenesulfonyl; Y is (i) (a) carboxylgroup, (b) a lower alkoxy (thio) carbonyl group having optionally one ormore substituent(s) selected from among(1) hydroxyl groups unsubstitutedor substituted with a lower alkanoyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl orcyclohexyloxycarbonyl, (2) C₁₋₄ alkoxy carbonyl groups, (3) carbamoylgroups unsubstituted or substituted with substituent(s) selected fromamong C₁₋₃ alkyl groups, C₃₋₆ cycloalkyl groups, phenyl group, benzylgroup, carboxyl group, methoxycarbonyl, ethoxycarbonyl, andpropoxycarbonyl, (4) phenyl and C₃₋₆ cycloalkyl groups, each of which isunsubstituted or substituted with substituent(s) selected from amongC₁₋₃ alkyl groups and C₁₋₃ alkoxy groups, (5) C₁₋₃ alkenyl groups, (6)5-membered heterocyclic groups having one to three oxygen atoms, whichmay have one or more substituent(s) selected from the group consistingof C₁₋₃ alkyl and oxo, or a fused ring formed by cooperating said5-membered heterocyclic group with a benzene ring, or (c)phenoxy(thio)carbonyl, 1-naphtoxy(thio)carbonyl or benzyloxy(thio)carbonyl; (ii) a hydroxyl group unsubstituted or substituted with (1) aC₁₋₄ alkyl group, (2) a C₃₋₆ cycloalkyl group, (3) a phenyl, 1-naphthyl,2-naphthyl, benzyl or phenethyl group each of which is unsubstituted orsubstituted with halogen atom(s) or carboxyl group(s) optionallyesterified with C₁₋₄ alkyl; (iii) an amino group, unsubstituted orsubstituted with (1) C₁₋₄ alkyl group(s), (2) C₃₋₆ cycloalkyl(s) or (3)phenyl, 1-naphthyl, 2-naphthyl, benzyl and phenethyl group(s) each ofwhich is unsubstituted or substituted with substituent(s) selected fromamong halogen atoms and carboxyl groups optionally esterified with C₁₋₄alkyl group in which the two substituents on the nitrogen atom may form,taken together with the nitrogen atom, a cyclic amino group; (iv) aphenyl group unsubstituted or substituted with substituents selectedfrom among (1) C₁₋₄ alkyl groups unsubstituted or substituted withsubstituent(s) selected from carboxyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl and sec-butoxycarbonyl,(2) C₁₋₄ alkoxy groups, (3)methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl and sec-butoxycarbonyl, (4) phenylgroups unsubstituted or substituted with substituent(s) selected fromcarboxyl group, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl andsec-butoxycarbonyl, (5) amino groups unsubstituted or substituted withC₁₋₃ alkyl group(s) and (6) tetrazol-5-yl,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl and2,5-dihydro-5-oxo-1,2,4thiadiazol-3-yl; (v) a carbamoyl groupunsubstituted or substituted with 1 to 2 substituent(s) selected fromamong(1) C₁₋₆ alkyl groups and C₃₋₆ cycloalkyl groups each of which isunsubstituted or substituted with 1 to 3 substituent(s) selected fromamong carboxyl groups optionally esterified the C₁₋₅ alkyl group, furyl,thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl,amino group, hydroxyl group and phenyl group, (2) aryl groups andaralkyl groups unsubstituted or substituted with substituent(s) selectedfrom among halogen atoms and carboxyl groups optionally esterified withC₁₋₄ alkyl groups, in which the two substituents on the nitrogen atommay form a cyclic amino group taken together with the nitrogen atom; or(vi) tetrazol-5-yl or a group represented by the formula ##STR260##wherein i stands for --O-- or --S--; j stands for ##STR261## providedthat, when X is methylene and R₁ is not an alkyl group having more than4 carbon atoms, Y is neither carboxyl group nor alkoxycarbonyl group;the ring A being optionally substituted by C₁₋₄ alkoxy or a halogenatom, or a pharmaceutically acceptable salt thereof.
 41. A method forthe prophylaxis or treatment of hypertriglyceridemia in a mammal in needthereof comprising administering to said mammal a pharmaceuticallyacceptable amount of a compound of formula (I') ##STR262## wherein R₁ is(i) hydrogen, (ii) a C₁₋₇ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group,(iii) a C₃₋₉ cycloalkyl group, a cycloalkenyl groupselected from among 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and1-cyclopenten-1-yl, a cycloalkadienyl group selected from among2,4-cyclopentadien-1-yl, 2,4 cyclohexadien-1-yl, and2,5-cyclohexadien-1-yl, or (iv) an aryl group selected from amongphenyl, naphthyl, anthryl, phenanthryl and acenaphythylenyl in whicheach of the group of (ii), (iii) and (iv) is unsubstituted orsubstituted with 1 to 5 substituent(s) selected from the groupconsisting of(1) phenyl, naphthyl, anthyl, phenanthryl, acenaphthylenyl,C₃₋₇ cycloalkyl groups and C₃₋₆ cycloalkenyl groups each of which isunsubstituted or substituted with 1 to 2 substituent(s) selected fromamong C₁₋₃ alkoxy groups and C₁₋₃ alkyl groups, (2) furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzob!thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, τ-carbolinyl, β-carbolinyl,π-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxthinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, 1,2,4-triazolo4,3-b!pyridazinyl, oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl or piperazinyl, each of said groups beingunsubstituted or substituted with C₁₋₃ alkyl, (3) amino groups, hydroxylgroups and thiol groups each of which is unsubstituted or substitutedwith C₁₋₃ alkyl groups and (4) halogen atoms; and having each of thegroups of (iii) and (iv) may further have a C₁₋₃ alkyl group, and (5)C₁₋₆ acyl groups; each of R₂ and R₃ is independently (i) hydrogen; (ii)a C₁₋₆ alkyl group unsubstituted or substituted with substituent(s)selected from among halogens and C₁₋₄ alkoxy groups; (iii) a phenylgroup unsubstituted or substituted by 1 to 3 substituent(s) selectedfrom among (1) halogen atoms, (2) C₁₋₄ alkyl groups unsubstituted orsubstituted with 1 to 3 halogen atoms, (3) C₁₋₄ alkoxy groupsunsubstituted or substituted with 1 to 3 halogen atoms, (4) hydroxylgroups unsubstituted or substituted with a C₁₋₄ alkyl group, a C₃₋₆cycloalkyl group, phenyl, 1-naphthyl, 2-naphthyl, benzyl or phenethyl,(5) nitro group and (6) cyano group in which the two adjoiningsubstituents on the phenyl group may cooperate therewith to form a ringwhich is unsubstituted or substituted with a C₁₋₃ alkyl or (iv) furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,π-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl or 1,2,4-triazolo4,3-b!pyridazinyl, each of said groups being unsubstituted orsubstituted with C₁₋₃ alkyl; X is a bond or a divalent chain representedby the formula ##STR263## wherein m and n denote independently 0, 1, 2or 3; E stands for a bond or oxygen atom, sulfur atom, sulfoxide,sulfone, ##STR264## wherein R₆ and R₇ independently stand for (i)hydrogen atoms (ii) a C₁₋₆ alkyl group unsubstituted or substituted withfuryl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl,isoindolyl, an amino group unsubstituted or substituted with C₁₋₃ alkylgroup(s), a hydroxyl group unsubstituted or substituted with a C₁₋₃alkyl group, a thiol group unsubstituted or substituted with a C₁₋₃alkyl group, carboxyl group, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, phenoxycarbonyl, 1-naphtoxycarbonyl or2-naphtoxycarbonyl or a halogen atom; (iii) benzyl, napthylmethyl,phenylethyl, phenylpropyl or phenylbutyl unsubstituted or substitutedwith substituent(s) selected from halogens, C₁₋₃ alkoxy groups, hydroxylgroup, amino group, carboxyl group and sulfhydryl or (iv) a phenyl groupunsubstituted or substituted with substituent(s) selected from halogenatoms and C₁₋₃ alkyl groups; R₅ stand for hydrogen atom, a C₁₋₄ alkyl, aC₇₋₁₅ aralkyl, a lower alkanoyl group, a lower alkenoyl group, a loweralkanesulfonyl group, benzoyl, p-toluoyl, 1-naphthoyl and 2-naphthoyl,phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl cinnamoyl,atropoyl, benzenesulfonyl or p-toluenesulfonyl; Y is (i) (a) carboxylgroup, (b) a lower alkoxy (thio) carbonyl group having optionally one ormore substituent(s) selected from among(1) hydroxyl groups unsubstitutedor substituted with a lower alkanoyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl orcyclohexyloxycarbonyl, (2) C₁₋₄ alkoxy carbonyl groups, (3) carbamoylgroups unsubstituted or substituted with substituent(s) selected fromamong C₁₋₃ alkyl groups, C₃₋₆ cycloalkyl groups, phenyl group, benzylgroup, carboxyl group, methoxycarbonyl and ethoxycarbonyl,propoxycarbonyl, (4) phenyl and C₃₋₆ cycloalkyl groups each of which isunsubstituted or substituted with substituent(s) selected from amongC₁₋₃ alkyl groups and C₁₋₃ alkoxy groups, (5) C₁₋₃ alkenyl groups, (6)5-membered heterocyclic groups having one to three oxygen atoms, whichmay have one or more substituent(s) selected from the group consistingof C₁₋₃ alkyl and oxo, or a fused ring formed by cooperating said5-membered heterocyclic group with a benzene ring, or (c)phenoxy(thio)carbonyl, 1-naphtoxy(thio)carbonyl or benzyloxy (thio)carbonyl; (ii) a hydroxyl group unsubstituted or substituted with (1) aC₁₋₄ alkyl group, (2) a C₃₋₆ cycloalkyl group, (3) a phenyl, 1-naphthyl,2-naphthyl, benzyl or phenethyl group each of which is unsubstituted orsubstituted with halogen atom(s) or carboxyl group(s) optionallyesterified with C₁₋₄ alkyl; (iii) an amino group, unsubstituted orsubstituted with (1) C₁₋₄ alkyl group(s), (2) C₃₋₆ cycloalkyl(s) or (3)phenyl, 1-naphthyl, 2-naphthyl, benzyl and phenethyl group(s) each ofwhich is unsubstituted or substituted with substituent(s) selected fromamong halogen atoms and carboxyl groups optionally esterified with C₁₋₄alkyl group in which the two substituents on the nitrogen atom may form,taken together with the nitrogen atom, a cyclic amino group; (iv) aphenyl group unsubstituted or substituted with substituents selectedfrom among (1) C₁₋₄ alkyl groups unsubstituted or substituted withsubstituent(s) selected from carboxyl group, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl and sec-butoxycarbonyl,(2) C₁₋₄ alkoxy groups, (3)methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl and sec-butoxycarbonyl, (4) phenylgroups unsubstituted or substituted with substituent(s) selected fromcarboxyl group, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl andsec-butoxycarbonyl, (5) amino groups unsubstituted or substituted withC₁₋₃ alkyl group(s) and (6) tetrazol-5-yl,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl and2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl; (v) a carbamoyl groupunsubstituted or substituted with 1 to 2 substituent(s) selected fromamong (1) C₁₋₆ alkyl groups and C₃₋₈ cycloalkyl groups each of which isunsubstituted or substituted with 1 to 3 substituent(s) selected fromamong carboxyl groups optionally esterified the C₁₋₅ alkyl group, furyl,thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl,amino group, hydroxyl group and phenyl group,(2) aryl groups and aralkylgroups unsubstituted or substituted with substituent(s) selected fromamong halogen atoms and carboxyl groups optionally esterified with C₁₋₄alkyl groups, in which the two substituents on the nitrogen atom mayform a cyclic amino group taken together with the nitrogen atom; or (vi)tetrazol-5-yl or a group represented by the formula ##STR265## wherein istands for --O-- or --S--; j stands for ##STR266## provided that, when Xis methylene, Y is neither carboxyl group nor alkoxycarbonyl group; thering A being optionally be substituted by C₁₋₄ alkoxy or a halogen atom,or a pharmaceutically acceptable salt thereof.